CN102307577A - Pharmaceutical composition comprising an SGLT2 inhibitor, a DPP-IV inhibitor and a third antidiabetic agent, and uses thereof - Google Patents

Pharmaceutical composition comprising an SGLT2 inhibitor, a DPP-IV inhibitor and a third antidiabetic agent, and uses thereof Download PDF

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Publication number
CN102307577A
CN102307577A CN2010800070254A CN201080007025A CN102307577A CN 102307577 A CN102307577 A CN 102307577A CN 2010800070254 A CN2010800070254 A CN 2010800070254A CN 201080007025 A CN201080007025 A CN 201080007025A CN 102307577 A CN102307577 A CN 102307577A
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inhibitor
patient
disease
glucose
diabetes
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P.艾克尔曼
M.马克
L.J.西曼
L.托马斯
U.布罗德尔
R.格雷姆普勒
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
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Abstract

The invention relates to a pharmaceutical composition according to the claim 1 comprising an SGLT2 inhibitor, a DPPIV inhibitor and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

Description

The medical composition and its use that comprises SGLT2 inhibitor, DPP-IV inhibitor and optional another kind of antidiabetic drug
Technical field
The present invention relates to comprise SGLT2 inhibitor, DPPIV inhibitor and be selected from the pharmaceutical composition of the third antidiabetic drug of G3 group hereinafter described, it is suitable for treating or prevents one or more especially to be selected from the disease of type i diabetes, type ii diabetes, glucose tolerance reduction, impaired fasting glucose and hyperglycemia.
In addition, the present invention relates in the patient who needs is arranged, realize the method for following purpose:
-prevention of metabolic obstacle, slow down this dysbolismus progress, postpone or treat this dysbolismus;
-improve glycemic control and/or reduce fasting plasma glucose, plasma glucose and/or glycosylated hemoglobin HbAlc after the meal;
-prevent, slow down, postpone or reverse glucose tolerance reduction, impaired fasting glucose, insulin resistance and/or metabolism syndrome and make progress into type ii diabetes;
-prevention be selected from diabetic complication disease or obstacle, slow down this disease or obstacle progress, postpone or treat this disease or obstacle;
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat;
-prevention or treatment pancreatic beta cell are degenerated and/or are improved and/or recover the function of pancreatic beta cell and/or recover insulin secretion function;
-prevent, slow down, postpone or treat by dystopy fat and accumulate disease or the disease that causes unusually;
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance;
-prevention transplant the diabetes (NODAT) of the new outbreak in back and/or transplant after metabolism syndrome (PTMS), slow down these diseases progress, postpone or treat these diseases;
-prevention, delay or minimizing NODAT and/or PTMS related complication comprise blood capillary and trunk disease and incident, transplant rejection, infection and death;
-treatment hyperuricemia and hyperuricemia associated conditions;
-treatment or prevention renal calculus;
-treatment hyponatremia;
These methods are characterised in that SGLT2 inhibitor, DPPIV inhibitor and the third optional antidiabetic drug combination or alternately administration of hereinafter definition.
In addition, the present invention relates to the SGLT2 inhibitor and be used for the purposes in the medicine of the said method of context in preparation.
In addition, the present invention relates to DDP IV inhibitor and be used for the purposes in the medicine of the said method of context in preparation.
In addition, the present invention relates to hereinafter defined the third antidiabetic drug and be used for the purposes in the medicine of the said method of context in preparation.
The invention still further relates to pharmaceutical composition of the present invention and be used for the purposes in the medicine of the said method of context in preparation.
Prior art
Type ii diabetes is the disease of increased popularity, and it significantly shortens because of high-frequency complication causes life expectancy.Because the microvascular complication that diabetes are relevant, type ii diabetes is the most common cause of blindness, renal failure and the amputation of adult onset in the industrial world at present.In addition, the existence of type ii diabetes is relevant with 2 to 5 times of cardiovascular disease risk increases.
After disease continues for a long time, most of type ii diabetes patients' oral therapy ultimate failure, and become insulin-dependent, must every day insulin injection and carry out repeatedly glucose measurement every day.
(United Kingdom Prospective Diabetes Study UKPDS) proves that only producing limited glycemic control with metformin, sulfonylureas or insulin strengthening treatment improves (HbAlc difference is about 0.9%) to the perspective diabetes study of Britain.In addition, even in the patient of intensive treatment group, glycemic control also significantly worsens in time, due to this degenerates owing to the β cell function.Important ground, the intensive treatment not remarkable minimizing with trunk complication (being cardiovascular event) is relevant.Therefore, many type ii diabetes patients still can not fully treat, in part because the restriction of long-term efficacy, toleration and the administration convenience of existing hyperglycemia therapy.
Oral antidiabetic thing commonly used includes, but is not limited to metformin, sulfonylureas, thiazolidinedione, row how (glinides) and alpha-glucosidase inhibitor in the therapy (for example a line or two gamma therapies and/or monotherapy or (initial or append (add-on)) combination treatment).
The high rate of treatment failure is the complication relevant with long-term hyperglycemia of height ratio among the type ii diabetes patient or the main cause of chronic injury (comprising blood capillary and trunk complication, for example diabetic nephropathy, retinopathy or neuropathy or cardiovascular complication).
Therefore, exist relevant to having with glycemic control, with the amelioration of disease characteristic relevant and with reduce the unsatisfied needs that good effects that cardiovascular morbidity and mortality rate be correlated with shows method, medicine and the pharmaceutical composition of the security situation of improvement simultaneously.
The SGLT2 inhibitor represents one type to be used to treat or to improve the novel drugs that type ii diabetes patient's glycemic control is researched and developed.The substituted benzene derivative of glucopyranosyl is disclosed as the SGLT2 inhibitor in the prior art, for example is disclosed among WO 01/27128, WO 03/099836, WO 2005/092877, WO2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO2007/128749, WO 2008/049923, WO 2008/055870, the WO 2008/055940.The substituted benzene derivative of glucopyranosyl drains derivant and conduct treatment diabetes as urinary system sugar medicine is proposed.
In other mechanism, the kidney of glucose filters and is absorbed with and helps the steady state blood plasma concentration of glucose, and therefore can be used as the anti-diabetic target spot.Pass renal epithelial cell again the glucose of the absorbing and filtering carrier (SGLT) that will cotransport through the sodium dependent glucose of the brush border membrane (brush-border membrane) that is arranged in tubule carry out along the sodium gradient.There is the different SGLT hypotype of at least three kinds of expression patterns and physicochemical characteristics.SGLT2 only is expressed in the kidney, and SGLT1 also finds expression in its hetero-organization like intestinal, colon, skeleton and cardiac muscle.Found that SGLT3 is the glucose induction apparatus in the intestinal Interstitial cell and do not have any transport function.Other gene relevant but that do not characterize as yet possibly promote further that also the kidney glucose absorbs again.Under the normal situation of blood sugar concentration, glucose is absorbed by the SGLT in the kidney fully again, and the absorbability again of kidney is saturated during greater than 10mM at concentration of glucose, thereby causes glycosuria (" diabetes ").This threshold concentration possibly suppressed to reduce because of SGLT2.Show that in the experiment of SGLT inhibitor phlorhizin (phlorizin) inhibition SGLT will partly suppress glucose and absorb to blood from Glomerular filtrate again, thereby cause the blood sugar concentration reduction and cause glycosuria.
DPP IV inhibitor representative is another kind of to be used to treat or to improve the novel drugs that type ii diabetes patient's glycemic control is researched and developed.
For example, DPP IV inhibitor and uses thereof is disclosed in WO 2002/068420; WO2004/018467; WO 2004/018468; WO 2004/018469; WO 2004/041820; WO2004/046148; WO 2005/051950; WO 2005/082906; WO 2005/063750; WO2005/085246; WO 2006/027204; WO 2006/029769; WO2007/014886; WO2004/050658; WO 2004/111051; WO 2005/058901; WO 2005/097798; WO2006/068163; WO 2007/071738; WO 2008/017670; WO 2007/054201; Among WO2007/128721 or the WO 2007/128761.
Goal of the invention
The object of the present invention is to provide prevention of metabolic obstacle (especially type ii diabetes), slow down pharmaceutical composition and method that this dysbolismus is made progress, postponed or treat this dysbolismus.
Another object of the present invention is to provide improve the patient that needs is arranged, the especially pharmaceutical composition and the method for type ii diabetes patient's glycemic control.
Although another object of the present invention is to provide improve and carried out antidiabetic medicine (for example metformin) although monotherapy or combination treatment but the glycemic control of having carried out two kinds of antidiabetic drugs still pharmaceutical composition and the method for inadequate patient's glycemic control.
Another object of the present invention is to prevention is provided, slow down or postpone glucose tolerance and reduce pharmaceutical composition and the method that (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome make progress into type ii diabetes.
Another object of the present invention is to provide disease or obstacle that prevention is selected from diabetic complication, slow down this disease or obstacle progress, postpone or treat the pharmaceutical composition and the method for this disease or obstacle.
Another object of the present invention is to be provided at the pharmaceutical composition and the method that reduce body weight or prevention weight increase among the patient who needs.
Another object of the present invention is to provide and have the new pharmaceutical composition of treating dysbolismus efficiently; These dysbolismus especially are that diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG) and/or hyperglycemia, and this pharmaceutical composition has good in splendid pharmacology and/or pharmacokinetics and/or physicochemical characteristics.
By contextual description and embodiment, those skilled in the art will understand other purpose of the present invention.
Summary of the invention
Within the scope of the present invention; Be surprisingly found out that at present the pharmaceutical composition that comprises SGLT2 inhibitor and DPP IV inhibitor and be selected from the third antidiabetic drug of G3 group hereinafter described can be advantageously used in prevention patient's dysbolismus, slow down this dysbolismus progress, postpones or treat this dysbolismus, especially improves patient's glycemic control.This has opened up the new treatment probability of treatment and prevention type ii diabetes, overweight, obesity, diabetic complication and close morbid state.
Therefore, in first aspect, the present invention provides and comprises following pharmaceutical composition:
(a) the SGLT2 inhibitor and
(b) the DPPIV inhibitor and
(c) be selected from the third antidiabetic drug of following G3 group: biguanide, thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor, GLP-1 analog or its pharmaceutically acceptable salt.
According to a further aspect in the invention;, the patient who needs provide prevention to be selected from following dysbolismus in being arranged; Slow down this dysbolismus progress; Postpone or treat the method for this dysbolismus: type i diabetes; Type ii diabetes; Glucose tolerance reduces (IGT); Impaired fasting glucose (IFG); Hyperglycemia; Postprandial hyperglycemia disease; Overweight; Obesity; Metabolism syndrome and gestational diabetes the method is characterized in that the SGLT2 inhibitor of contextual definition; DPPIV inhibitor and optional the third antidiabetic drug (for example) give the patient to make up or to replace (alternation).
According to a further aspect in the invention; In the patient who needs is arranged, provide and improve glycemic control and/or reduce fasting plasma glucose, the method for plasma glucose and/or glycosylated hemoglobin HbAlc after the meal, SGLT2 inhibitor, DPPIV inhibitor and optional the third antidiabetic drug (for example) that the method is characterized in that contextual definition is with combination or alternately give the patient.
Pharmaceutical composition of the present invention also can have valuable amelioration of disease characteristic for reducing (IGT), impaired fasting glucose (IFG), insulin resistance and/or relevant disease or the disease of metabolism syndrome with glucose tolerance.
According to a further aspect in the invention; In the patient who needs is arranged, prevention is provided, slows down, postpones or reverses glucose tolerance and reduce the method that (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome make progress into type ii diabetes, the method is characterized in that SGLT2 inhibitor, the DPPIV inhibitor of contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give the patient.
The pharmaceutical composition of the application of the invention can improve glycemic control in the patient who needs is arranged, also can treat with blood sugar level increases those diseases and/or disease relevant or that caused by this increase.
According to a further aspect in the invention;, the patient who needs provide prevention to be selected from following disease or obstacle in being arranged; Slow down this disease or obstacle progress; Postpone or treat the method for this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease; Nephropathy for example; Retinopathy; Neuropathy; Tissue ischemia; Diabetic foot; Arteriosclerosis; Myocardial infarction; Acute coronary syndrome; Unstable angina pectoris; Stable angina pectoris; Apoplexy; Peripheral occlusive arterial disease; Cardiomyopathy; Heart failure; Arrhythmia and vascular restenosis the method is characterized in that the SGLT2 inhibitor of contextual definition; The DPPIV inhibitor reaches optional the third antidiabetic drug (for example) to make up or alternately to give the patient.Especially one or more aspects of treatment of diabetic nephropathy but (for example hyperperfusion, albuminuria and albuminuria), slow down its progress or postpone or prevent its outbreak.Term " tissue ischemia " especially comprises diabetic macroangiopathy, diabetic microangiopathy, wound healing and reaches diabetic ulcer unusually.Term " blood capillary and trunk disease " reaches " blood capillary and trunk complication " and is used interchangeably in this application.
Through administration pharmaceutical composition of the present invention and because the activity of SGLT2 inhibitor, the blood glucose of excessive levels can not change into insoluble storage form (like fat), but through patient's homaluria.In the animal model that uses the SGLT2 inhibitor, visible fat reduces the major part that accounts for viewed body weight reduction, and does not observe the significant change of body moisture or protein content.Therefore, the result does not increase for body weight or even body weight reduction.
According to a further aspect in the invention; The method that in the patient who needs is arranged, provides reduction body weight and/or body fat or prevention body weight and/or body fat increase or promotion to reduce body weight and/or body fat the method is characterized in that SGLT2 inhibitor, the DPPIV inhibitor of contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give the patient.
The pharmacological effect of the SGLT2 inhibitor in the pharmaceutical composition of the present invention and insulin are irrelevant.Therefore, might under the situation that pancreatic beta cell is not produced additional injuries, improve glycemic control.Through administration pharmaceutical composition of the present invention, can postpone or prevent β cell degradation and β cell function to reduce the for example apoptosis of pancreatic beta cell or necrosis.In addition, the function of pancreatic cell be can improve or recover, and the quantity and the size of pancreatic beta cell increased.Its demonstration can make the differentiation state and the hypertrophy normalization of the pancreatic beta cell of hyperglycemia upset through handling with pharmaceutical composition of the present invention.
According to a further aspect in the invention; In the patient who needs is arranged, prevention is provided, slows down, postpones or treat that pancreatic beta cell is degenerated and/or the pancreatic beta cell function reduces and/or improves and/or recover the pancreatic beta cell function and/or recover the method for insulin secretion function, SGLT2 inhibitor, the DPPIV inhibitor that the method is characterized in that contextual definition reaches the third antidiabetic drug (for example) of choosing wantonly to make up or alternately to give the patient.
Through administration combination of the present invention or pharmaceutical composition, can reduce or suppress accumulating unusually of dystopy fat (ectopic fat) (the especially dystopy of liver fat).Therefore; According to a further aspect in the invention; In the patient who needs is arranged, prevention is provided, slows down, postpones or treat the disease that caused by accumulating unusually of dystopy fat (the especially dystopy of liver fat) or the method for disease, SGLT2 inhibitor, the DPPIV inhibitor that the method is characterized in that contextual definition reaches the third antidiabetic drug (for example) of choosing wantonly to make up or alternately to give the patient.Unusually accumulating the disease or the disease that cause by liver fat especially is selected from: and general fatty liver (general fatty liver), non-alcoholic fatty liver disease (NAFL), non-alcoholic fatty degeneration hepatitis (non-alcoholic steatohepatitis, NASH), the supernutrition fatty liver, diabetic fatty liver, the ethanol that the bring out fatty liver or the toxic fatty liver that bring out.
Thus; Another aspect of the present invention provides the method that keeps and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance in the patient who needs is arranged, SGLT2 inhibitor, DPPIV inhibitor and optional the third antidiabetic drug (for example) that the method is characterized in that contextual definition is with combination or alternately give the patient.
According to a further aspect in the invention; In the patient who needs is arranged, provide prevention transplant the diabetes (NODAT) of the new outbreak in back and/or transplant after metabolism syndrome (PTMS), slow down these diseases progress, postpone or treat the method for these diseases, SGLT2 inhibitor, DPPIV inhibitor and optional the third antidiabetic drug (for example) that the method is characterized in that contextual definition is with combination or alternately give the patient.
According to a further aspect in the invention; Prevention is provided in the patient who needs is arranged, postpones or reduce the method for NODAT and/or PTMS related complication (comprising blood capillary and trunk disease and incident, transplant rejection, infection and death), SGLT2 inhibitor, DPPIV inhibitor and optional the third antidiabetic drug (for example) of the method is characterized in that contextual definition are to make up or alternately to give the patient.
Pharmaceutical composition of the present invention can promote the reduction of the total urate content of patients serum.Therefore; According to a further aspect in the invention; The method of treatment hyperuricemia and hyperuricemia associated conditions (for example gout, hypertension and renal failure) is provided in the patient who needs is arranged, the method is characterized in that SGLT2 inhibitor, the DPPIV inhibitor of contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give the patient.The patient can be diabetics or ND.
Give the homaluria that pharmaceutical composition increases glucose.The reduction of this increase that infiltration is drained and water discharges and urate content is useful to the treatment or the prevention of renal calculus.Therefore; In another aspect of this invention; The method of treatment or prevention renal calculus is provided in the patient who needs is arranged, and SGLT2 inhibitor, DPPIV inhibitor and optional the third antidiabetic drug (for example) that the method is characterized in that contextual definition is with combination or alternately give the patient.
According to a further aspect in the invention; The method of hyponatremia, water retention (water retention) and the water intoxication (water intoxication) of treatment is provided in the patient who needs is arranged, the method is characterized in that SGLT2 inhibitor, the DPPIV inhibitor of contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give the patient.Through giving pharmaceutical composition of the present invention, might reverse water retention through kidney is worked and reach and these diseases and the relevant electrolyte imbalance of disease, reverse the effect of hyponatremia, water retention and water intoxication.
According to a further aspect in the invention, the purposes of SGLT2 inhibitor is provided, it is used for preparing the medicine of realizing following purpose the patient that needs are arranged:
-prevention is selected from following dysbolismus, slows down this dysbolismus progress, postpones or treat this dysbolismus: type i diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia disease, overweight, obesity, metabolism syndrome and gestational diabetes; Or
-improve glycemic control and/or reduce fasting plasma glucose, plasma glucose and/or glycosylated hemoglobin HbAlc after the meal; Or
-prevent, slow down, postpone or reverse glucose tolerance reduction (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome and make progress into type ii diabetes; Or
-prevention is selected from following disease or obstacle, slows down this disease or obstacle progress, postpones or treat this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease, for example nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease; Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat; Or
-prevent, slow down, postpone or treat pancreatic beta cell degeneration and/or the reduction of pancreatic beta cell function, and/or improve and/or recovery pancreatic beta cell function and/or recovery insulin secretion function; Or
-prevent, slow down, postpone or treat by dystopy fat and accumulate disease or the disease that causes unusually; Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance;
-prevention transplant the diabetes (NODAT) of the new outbreak in back and/or transplant after metabolism syndrome (PTMS), slow down its progress, delay or treat these diseases;
-prevention, delay or minimizing NODAT and/or PTMS related complication comprise blood capillary and trunk disease and incident, transplant rejection, infection and death;
-treatment hyperuricemia and hyperuricemia associated conditions;
-treatment or prevention renal calculus;
-treatment hyponatremia;
This purposes is characterised in that the DPP IV inhibitor of this SGLT2 inhibitor and contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give.
According to a further aspect in the invention, the purposes of the DPP IV inhibitor of contextual definition is provided, it is used for preparing the medicine of realizing following purpose the patient that needs are arranged:
-prevention is selected from following dysbolismus, slows down this dysbolismus progress, postpones or treat this dysbolismus: type i diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia disease, overweight, obesity and metabolism syndrome; Or
-improve glycemic control and/or reduce fasting plasma glucose, plasma glucose and/or glycosylated hemoglobin HbAlc after the meal; Or
-prevent, slow down, postpone or reverse glucose tolerance reduction (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome and make progress into type ii diabetes; Or
-prevention is selected from following disease or obstacle, slows down this disease or obstacle progress, postpones or treat this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease, for example nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease; Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat; Or
-prevent, slow down, postpone or treat pancreatic beta cell degeneration and/or the reduction of pancreatic beta cell function, and/or improve and/or recovery pancreatic beta cell function and/or recovery insulin secretion function; Or
-prevent, slow down, postpone or treat by liver fat and accumulate disease or the disease that causes unusually; Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance;
This purposes is characterised in that the SGLT2 inhibitor of this DPP IV inhibitor and contextual definition reaches optional the third antidiabetic drug (for example) to make up or alternately to give.
According to a further aspect in the invention, the purposes of the third antidiabetic drug of contextual definition is provided, it is used for preparing the medicine of realizing following purpose the patient that needs are arranged:
The following dysbolismus of-prevention, slow down this dysbolismus progress, postpone or treat this dysbolismus: type i diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia disease, overweight, obesity and metabolism syndrome; Or
-improve glycemic control and/or reduce fasting plasma glucose, plasma glucose and/or glycosylated hemoglobin HbAlc after the meal; Or
-prevent, slow down, postpone or reverse glucose tolerance reduction (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome and make progress into type ii diabetes; Or
-prevention is selected from following disease or obstacle, slows down this disease or obstacle progress, postpones or treat this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease, for example nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease; Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat; Or
-prevent, slow down, postpone or treat pancreatic beta cell degeneration and/or the reduction of pancreatic beta cell function, and/or improve and/or recovery pancreatic beta cell function and/or recovery insulin secretion function; Or
-prevent, slow down, postpone or treat by liver fat and accumulate disease or the disease that causes unusually; Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance;
SGLT2 inhibitor and the DPPIV inhibitor (for example) that this purposes is characterised in that this third antidiabetic drug and contextual definition is with combination or alternately give.
According to a further aspect in the invention, the purposes of pharmaceutical composition of the present invention is provided, it is used to prepare the medicine that is used for described therapeutic of context and prophylactic methods.
Definition
The term of pharmaceutical composition of the present invention " active ingredient " is meant SGLT2 inhibitor of the present invention and/or DPP IV inhibitor.
The term of human patients " Body Mass Index " or " BMI " be defined as in the body weight of kilogram divided by in the height of rice square, so the unit of BMI is kg/m 2
Term " overweight " is defined as individual BMI greater than 25kg/m 2And less than 30kg/m 2Disease.Term " overweight " reaches " in earlier stage fat " and is used interchangeably.
Term " obesity " is defined as individual BMI and is equal to or greater than 30kg/m 2Disease.According to the WHO definition, the term obesity can be classified as follows: term " I level obesity " is equal to or greater than 30kg/m for BMI 2But less than 35kg/m 2Disease; Term " II level obesity " is equal to or greater than 35kg/m for BMI 2But less than 40kg/m 2Disease; Term " III level obesity " is equal to or greater than 40kg/m for BMI 2Disease.
Term " visceral obesity " be defined as measure male's waist-to-hipratio more than or equal to 1.0 and women's waist-to-hipratio more than or equal to 0.8 disease.The risk of its definition insulin resistance and pre-diabetes development.
Term " abdominal fatness " is commonly defined as the disease of male's waistline＞40 inch or 102cm and women's waistline＞35 inch or 94cm.With regard to Japan race (Japanese ethnicity) or Japanese patients, abdominal fatness may be defined as male waistline >=85cm and women waistline >=90cm (for example diagnosing enquiry committee (investig a ting committee for the diagnosis of metabolic syndrome in Japan) referring to Japanese metabolism syndrome).
Term " blood glucose is normal " is defined as individual fasting glucose concentration in normal range, promptly greater than 70mg/dL (3.89mmol/L) and less than the situation of 100mg/dL (5.6mmol/L)." on an empty stomach " speech has the general sense of medical terminology.
Term " hyperglycemia " is defined as individual fasting glucose concentration and is higher than normal range, promptly greater than the disease of 100mg/dL (5.6mmol/L)." on an empty stomach " speech has the general sense of medical terminology.
Term " hypoglycemia " is defined as individual blood sugar concentration and is lower than normal range, especially less than the disease of 70mg/dL (3.89mmol/L).
Term " postprandial hyperglycemia disease " is defined as 2 hours after the meal blood glucose of individuality or the serum glucose concentration disease greater than 200mg/dL (11.11mmol/L).
Term " impaired fasting glucose " or " IFG " be defined as individual fasting glucose concentration or on an empty stomach serum glucose concentration in 100 to 125mg/dl (promptly 5.6 to 6.9mmol/l) scope, especially greater than 110mg/dL and less than the disease of 126mg/dl (7.00mmol/L).The fasting glucose concentration of " normal fasting glucose " individuality is less than 100mg/dl, promptly less than 5.6mmol/l.
Term " glucose tolerance reduction " or " IGT " are defined as 2 hours after the meal blood glucose of individuality or serum glucose concentration greater than 140mg/dl (7.78mmol/L) and less than the disease of 200mg/dL (11.11mmol/L).Unusual glucose tolerance (promptly 2 hours after the meal blood glucose or serum glucose concentration) can be with after the back picked-up 75g glucose on an empty stomach 2 hours, and per minute rises the blood sugar content of the glucose in milligrams number of blood plasma and measures." normal glucose toleration " individual 2 hours after the meal blood glucose or serum glucose concentration are less than 140mg/dl (7.78mmol/L).
Term " hyperinsulinemia " be defined as have insulin resistance and blood glucose is normal or the empty stomach of the undesired individuality of blood glucose or after the meal serum or plasma insulin concentration be higher than no insulin resistance and waist-to-hipratio＜1.0 (male) or＜disease of the normal thin individuality of 0.8 (women).
Term " insulin sensitivity ", " insulin resistance improvement " or " insulin resistance reduction " synonym and be used interchangeably.
Term " insulin resistance " is defined as the insulin content that wherein need circulate and surpasses normal reaction that glucose is stimulated with the state that keeps the euglycemia state people such as (, JAMA. (2002) 287:356-9) Ford ES.The method of measuring insulin resistance is euglycemia-hyperinsulinemia property clamp test (euglycaemic-hyperinsulinaemic clamp test).In combination insulin-glucose infusion technical scope, measure the ratio of insulin and glucose.If glucose absorption is lower than 25% of the background population of studying, then think to have insulin resistance (WHO definition).Much simpler and easy that is so-called mini model (minimal model) than clamp test, wherein during the intravenous glucose tolerance test, insulin and concentration of glucose under Fixed Time Interval in the measurement blood, and calculate insulin resistance thus.Can not difference liver insulin resistance and periphery insulin resistance with the method.
In addition; Can come quantitative insulin resistance (being the reaction of tool insulin resistance patient), insulin sensitivity and hyperinsulinemia (people such as KatsukIA, Diabetes Care 2001 through the evaluation steady-state model of the insulin resistance " evaluation (HOMA-IR) " score (the reliable indication of insulin resistance) to therapy; 24:362-5).Also with reference to measuring the exponential method of the HOMA (people such as Matthews of insulin sensitivity; Diabetologia 1985; 28:412-19), measure the method (people such as Forst of the ratio of complete proinsulin and insulin; Diabetes 2003,52 (supplementary issue 1): A459) and euglycemia clamp research.In addition, can possibly substituting of insulin sensitivity monitor blood plasma adiponectin (adiponectin) content.Calculate stable state evaluation model (HOMA)-IR score to the estimation of insulin resistance (people such as Galvin P, Diabet Med 1992 with following formula; 9:921-8):
HOMA-IR=[is serum insulin (μ U/mL) on an empty stomach] * [fasting plasma glucose (mmol/L)/22.5]
Usually, in clinical practice every day, use other parameter evaluation insulin resistance.Preferably, use for example patient's triglyceride concentration because the increase of content of triglyceride and insulin resistance have a tool significant correlation property.
The patient of tool development IGT or IFG or type ii diabetes tendency has hyperinsulinemia for those and is defined as the normal person of blood glucose of insulin resistant.Typical patient with insulin resistance is general overweight or fat.If can detect insulin resistance, then this is the brute force indication that pre-diabetes occurs.Therefore, in order to keep the glucose stable state, this individuality possibly need healthy individual 2-3 insulin doubly, otherwise will cause any clinical symptoms.
The method of research pancreatic beta cell function with above about insulin sensitivity; The method of hyperinsulinemia or insulin resistance is similar: can be for example HOMA index (people such as Matthews through measuring the β cell function; Diabetologia 1985; 28:412-19); The ratio of complete proinsulin and insulin (people such as Forst; Diabetes 2003; 52 (supplementary issues 1): A459); Insulin behind oral glucose tolerance test or the meal tolerance test/C-peptide secretion; Or through adopting the research of hyperglycemia clamp and/or behind the intravenous glucose tolerance test of frequent sampling, setting up mini model (people such as Stumvoll; Eur J Clin Invest 2001 31:380-81) measures the improvement of β cell function.
Term " pre-diabetes " is the individual disease of tending to develop type ii diabetes.Pre-diabetes has been expanded the definition that glucose tolerance reduces, make it comprise have fasting glucose high normal range (>=100mg/dL) in (people such as J.B.Meigs, Diabetes 2003; 52:1475-1484) and have an on an empty stomach individuality of hyperinsulinemia (high plasma insulin concentration).ADA (American Diabetes Association) and the state-run diabetes of the U.S. and digestion and nephropathy institute (National Institute of Diabetes and Digestive and Kidney Diseases) are set forth in the status report that is entitled as " The Prevention or Delay of Type 2 Diabetes " of common issue and are differentiated that pre-diabetes is healthy science and basic medical (Diabetes Care 2002 of serious threat; 25:742-749).
The individuality that possibly have insulin resistance is the individuality with two or more following characteristics: 1) overweight or fat, 2) hypertension, 3) hyperlipemia, 4) diagnosis of one or more first degree relatives suffers from IGT or IFG or type ii diabetes.Can confirm the insulin resistance that these are individual through calculating the HOMA-IR score.For purposes of the present invention, insulin resistance is defined as individual HOMA-IR score＞4.0 or HOMA-IR score and is higher than laboratory and carries out the clinical disease that glucose and insulin are analyzed defined upper limits of normal.
Term " type ii diabetes " is defined as individual fasting glucose or the serum glucose concentration disease greater than 125mg/dL (6.94mmol/L).Blood glucose value be measured as the standard operation in the conventional medical analysis.If carry out glucose tolerance test, then the blood sugar content of diabetics will rise blood plasma 200mg glucose (11.1mmol/l) above 2 hours per minutes after absorbing the 75g glucose on an empty stomach.In glucose tolerance test, after empty stomach 10-12 hour to patient's orally give 75g glucose to be measured, and 1 hour and 2 hour record blood sugar contents before being about to ingestion of glucose and after the ingestion of glucose.In healthy individual, the blood sugar content before the ingestion of glucose will rise blood plasma 60mg to 110mg for per minute, and after the ingestion of glucose 1 hour, will be less than 200mg/dL, and absorbed back 2 hours, will be less than 140mg/dL.Be 140mg to 200mg as if absorbing back 2 hours, and being worth, then this is regarded as abnormal glucose tolerance.
Term " type ii diabetes in late period " comprises Secondary cases drug failure, tool insulin treatment indication and makes progress into blood capillary and the trunk complication (patient of diabetic nephropathy or coronary heart disease (CHD) for example.
Term " HbAlc " is meant the glycosylated product of the non-enzymatic of hemoglobin B chain.Those skilled in the art know its mensuration.When the monitoring treatment of diabetes, the HbAlc value is even more important.Because blood sugar content and erythrocytic life-span are depended in the generation of HbAlc basically, so the average blood sugar content in 4-6 week before HbAlc reflects on " blood glucose memory " meaning.The diabetics of well-tuned (promptly less than the total hemoglobin of sample 6.5%) is protected significantly better and avoid diabetic microangiopathy all the time by the diabetes intensive treatment for the HbAlc value.For example, metformin itself on average is improved as about 1.0-1.5% to what the HbAlc value of diabetics reached.In all diabeticss, this HbAlc value reduces the required target zone that is not enough to reach HbAlc＜6.5% and preferred＜6%.
In the scope of the invention, term " inadequate glycemic control " or " insufficient glycemic control " are meant that the patient shows that the HbAlc value is higher than 6.5%, especially is higher than 7.0% even more be higher than 7.5%, especially be higher than 8% situation.
" metabolism syndrome " also is called " X syndrome " (under the dysbolismus situation, using), also is called " the bad syndrome of metabolism ", and its principal character is syndrome (people such as Laaksonen DE, the Am J Epidemiol 2002 of insulin resistance; 156:1070-7).According to ATPIII/NCEP guilding principle (ExecutiveSummaryoftheThirdReportoftheNationalCholesterol EducationProgram(NCEP) ExpertPanelonDetection; Evaluation; AndTreatmentofHighBloodCholesterolinAdults(AdultTreatmen tPanelIII) 285:2486-2497 JAMA:JournaloftheAmericanMedicalAssociation(2001)); When having three or more following risk factors, be diagnosed as metabolic syndrome:
1. abdominal fatness, it is defined as male's waistline＞40 inch or 102cm and women's waistline＞35 inch or 94cm; Or with regard to Japanese race or Japanese patients, be defined as male waistline >=85cm and women waistline >=90cm;
2. triglyceride: >=150mg/dL
3. male HDL-cholesterol＜40mg/dL
4. blood pressure >=130/85mm Hg (SBP >=130 or DBP >=85)
5. fasting glucose >=100mg/dL
Verified NCEP definition people such as (, Am J Epidemiol. (2002) 156:1070-7) Laaksonen DE.Also can be by Thomas L (volume) in the medical analysis and for example: " Labor und Diagnose "; TH-Books Verlagsgesellschaft mbH; Frankfurt/Main, triglyceride in blood and HDL cholesterol are measured in the standard method of describing in 2000.
According to common definition,, then be diagnosed as hypertension if systolic pressure (SBP) surpasses 140mm Hg and diastolic pressure (DBP) surpasses 90mm Hg.If the patient suffers from overt diabetes (manifest diabetes), then recommend systolic pressure to be brought down below the degree that 130mm Hg and diastolic pressure are brought down below 80mm Hg at present.
Definition and International Diabetes Federation (the International Diabetes Federation of ADA (American Diabetes Association) about the type ii diabetes diagnostic criteria followed in NODAT (transplanting the diabetes of the new outbreak in back) and the definition of PTMS (metabolism syndrome after the transplanting) closely; IDF) and American Heart Association/American National heart, lung and Blood Research Institute (American Heart Association/National Heart; Lung, and Blood Institute) about the definition of metabolism syndrome.NODAT and/or PTMS increase relevant with the risk of blood capillary and trunk disease and incident, transplant rejection, infection and death.Differentiated the predictor of the multiple potential risk factor relevant with NODAT and/or PTMS, comprise Body Mass Index before age higher when transplanting, male gender, the transplanting, transplant before diabetes and immunosuppressant.
Term " gestational diabetes " (diabetes period of pregnancy) expression phenolics development and the diabetes form that generally after production, stops immediately again.By diagnosing gestational diabetes at the conceived filler test that carried out in the 24th thoughtful the 28th week.It is generally simple test, and wherein after giving the 50g glucose solution 1 hour, measuring blood content.If this 1 hour content is higher than 140mg/dl, then doubts and suffer from gestational diabetes.Can confirm by SGTT (for example using the 75g glucose) is final.
The disease of the total urate content of term " hyperuricemia " the high serum of expression.In human blood, American Medical Association (American Medical Association) think 3.6mg/dL (about 214 μ mol/L) to the uric acid concentration of 8.3mg/dL (about 494 μ mol/L) for normal.Total urate content of high serum or hyperuricemia are relevant with multiple disease usually.For example, the total urate content of high serum can produce one type of arthritis that is called gout in the joint.Gout is for forming the disease that monosodium urate or uric acid crystal are produced on the articular cartilage in the joint, tendon and the surrounding tissue that are caused by the total urate content of the high concentration in the blood flow.Form the inflammatory reaction that urates or uric acid excite these tissues at these tissues.When uric acid or urate in kidney during crystallization, the uric acid of saturated content can cause forming renal calculus in the urine.In addition, the total urate content of high serum is relevant with so-called metabolism syndrome (comprising cardiovascular disease and hypertension) usually.
Term " hyponatremia " expression lacks sodium or has no lack of the disease of the water positive balance of sodium, reduces to 135mml/L content when following when plasma sodium, is considered as hyponatremia.The disease of hyponatremia for can in consuming the individuality of water excessively, independently occurring; Yet hyponatremia is more typically and causes water to drain the Drug therapy complication of minimizing or the complication of other preclinical medicine disease.Hyponatremia can cause the water intoxication that takes place because of the excessive water retention, reduces to margin of safety when the normal tension (tonicity) of extracellular fluid body and takes place when following.Water intoxication is the potential fatal interference of brain function.That the classical symptom of water intoxication comprises is nauseating, vomiting, headache and uncomfortable.
Term " SGLT2 inhibitor " in the scope of the invention is meant that especially human SGLT2 shows inhibiting chemical compound, especially refers to the Glucopyranose. radical derivative, promptly has the chemical compound of Glucopyranose. base section to sodium-glucose transport carrier 2 (SGLT2).With IC 50The inhibitory action of measuring to hSGLT2 preferably is lower than 1000nM, even more preferably less than 100nM, most preferably is lower than 50nM.The IC of SGLT2 inhibitor 50Value is generally greater than 0.01nM, or even is equal to or greater than 0.1nM.Can measure inhibitory action by known method in the document, especially the method described in application WO 2005/092877 or WO2007/093610 (the 23/24th page) (it is incorporated herein by reference in full) to hSGLT2.Term " SGLT2 inhibitor " also comprises any its pharmaceutically acceptable salt, its hydrate and solvate, comprises crystal form out of the ordinary.
Term " DPPIV inhibitor " in the scope of the invention is meant the enzyme DPP IV is shown the active chemical compound of inhibition.This suppresses activity can be by IC 50Value characterizes.The IC that the DPPIV inhibitor is shown 50Value preferably is lower than 10000nM, preferably is lower than 1000nM.The IC that concrete DPPIV inhibitor is shown 50Value is lower than 100nM, or even≤50nM.The IC of DPPIV inhibitor 50Be worth generally greater than 0.01nM, or even greater than 0.1nM.The DPPIV inhibitor can comprise biology and non-biological compound, especially non-peptide compound.Can measure inhibitory action by known method in the document, especially the method described in application WO02/068420 or WO 2004/018468 (the 34th page) (it is incorporated herein by reference in full) to DPPIV.Term " DPPIV inhibitor " also comprises any its pharmaceutically acceptable salt, its hydrate and solvate, comprises crystal form out of the ordinary.
Term " treatment " comprises the patient that this disease (especially dominant form) appearred in therapeutic treatment.Therapeutic treatment can be the The Symptom of Symptoms treatment that alleviates concrete indication, or reverses or part reverses the situation of indication or stops or the cause of disease of slowing down progression of disease is handled.Therefore, the present composition and method can be used as for example therapeutic treatment and the extended regimen of a period of time.
Term " preventative processing " reaches " prevention " and is used interchangeably, and comprises the patient in the risk that is in development disease mentioned above, thereby reduces this risk.
Description of drawings
Fig. 1 shows the glucose fluctuation of the glucose AUC of Zucker rat, wherein gives SGLT2 inhibitor (A), DPPIV inhibitor (B), metformin (Met) and combination (A+Met, B+Met, A+B, A+B+Met) thereof to these rats.
Detailed Description Of The Invention
Aspect of the present invention, especially pharmaceutical composition, method and purposes are meant SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug of contextual definition.In the inventive method and purposes, optional the third antidiabetic drug that gives, i.e. the third antidiabetic drug of SGLT2 inhibitor and DPPIV inhibitor combination gives or does not make up the third antidiabetic drug to give.In the inventive method and purposes, SGLT2 inhibitor and the third antidiabetic drug of DPPIV inhibitor preferred compositions give.
The SGLT2 inhibitor is preferably selected from following G1 group: Da Gelie clean (dapagliflozin), Kan Gelie clean (canagliflozin), A Gelie clean (atigliflozin), Rui Gelie clean (remogliflozin), She Gelie clean (sergliflozin) and the substituted benzene derivative of formula (I) glucopyranosyl
Figure BDA0000081995560000171
R wherein 1Expression Cl, methyl or cyanic acid, R 2Expression H, methyl, methoxyl group or hydroxyl and R 3Expression ethyl, cyclopropyl, acetenyl, ethyoxyl, (R)-oxolane-3-base oxygen base or (S)-oxolane-3-base oxygen base; Or the prodrug of above-mentioned a kind of SGLT2 inhibitor.
Formula (I) chemical compound and synthesis method thereof are described in the for example following patent application: WO2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO2008/055870.
In the substituted benzene derivative of formula (I) glucopyranosyl above, preferred following substituent group definition.
R 1Preferred expression chlorine or cyanic acid, especially chlorine.
R 2Preferred expression H.
R 3Preferred expression ethyl, cyclopropyl, acetenyl, (R)-oxolane-3-base oxygen base or (S)-oxolane-3-base oxygen base.R 3Even more preferably representative ring propyl group, acetenyl, (R)-oxolane-3-base oxygen base or (S)-oxolane-3-base oxygen base.R 3Most preferably represent acetenyl, (R)-oxolane-3-base oxygen base or (S)-oxolane-3-base oxygen base.
The preferred substituted benzene derivative of formula (I) glucopyranosyl is selected from chemical compound (I.1) to (I.11):
Figure BDA0000081995560000181
Figure BDA0000081995560000191
Figure BDA0000081995560000201
Even the substituted benzene derivative of preferred formula (I) glucopyranosyl is selected from chemical compound (I.6), (I.7), (I.8), (I.9) and (I.11).
Therefore, G1 group is preferably clean by Da Gelie, Rui Gelie clean, chemical compound (I.6), chemical compound (I.7), chemical compound (I.8), chemical compound (I.9) and chemical compound (I.11) are formed.
G1 organizes even more preferably reaches chemical compound (I.9) only by Da Gelie and forms.
According to the present invention, should be appreciated that the definition of the substituted benzene derivative of above listed formula (I) glucopyranosyl also comprises its hydrate, solvate and polymorphic thereof, and prodrug.About preferred compound (I.7), favourable crystal form is described in the International Patent Application WO 2007/028814, and it is incorporated herein by reference in full.About preferred compound (I.8), favourable crystal form is described in the International Patent Application WO 2006/117360, and it is incorporated herein by reference in full.About preferred compound (I.9), favourable crystal form is described in the International Patent Application WO 2006/117359, and it is incorporated herein by reference in full.About preferred compound (I.11), favourable crystal form is described in the International Patent Application WO 2008/049923, and it is incorporated herein by reference in full.These crystal forms have good dissolubility property, and it gives the SGLT2 inhibitor good bioavailability.In addition, crystal form is that physical chemistry is stable, and therefore provides pharmaceutical composition good storage period stability.
Term as used herein " Da Gelie is clean " is meant that Da Gelie is clean, comprises its hydrate and solvate, and crystal form.Chemical compound and synthesis method thereof for example are described among the WO 03/099836.Preferred water compound, solvate and crystal form for example are described among the patent application WO 2008/116179 and WO 2008/002824.
Term as used herein " Kan Gelie is clean " is meant that Kan Gelie is clean, comprises its hydrate and solvate, and crystal form, and has following structure:
Figure BDA0000081995560000211
Chemical compound and synthesis method thereof for example are described among the WO 2005/012326 and WO 2009/035969.Preferred water compound, solvate and crystal form for example are described among the patent application WO 2008/069327.
Term as used herein " A Gelie is clean " is meant that A Gelie is clean, comprises its hydrate and solvate, and crystal form.Chemical compound and synthesis method thereof for example are described among the WO 2004/007517.
Term as used herein " Rui Gelie is clean " is meant that Rui Gelie reaches the clean prodrug of Rui Gelie (especially according to carbonic acid Rui Gelie clean (remogliflozin etabonate)) only, comprises its hydrate and solvate, and crystal form.Its synthesis method for example is described among the patent application EP 1213296 and EP 1354888.
Term as used herein " She Gelie is clean " is meant that She Gelie reaches the clean prodrug of She Gelie (especially clean according to carbonic acid She Gelie) only, comprises its hydrate and solvate, and crystal form.Its preparation method for example is described among the patent application EP 1344780 and EP 1489089.
For avoiding any query, the disclosure of aforementioned each document of above quoting relevant with specific SGLT2 inhibitor is incorporated herein by reference with it in full.
Aspect of the present invention, especially pharmaceutical composition, method and purposes are meant DPPIV inhibitor or its prodrug of contextual definition or its pharmaceutically acceptable salt.
The DPPIV inhibitor be preferably selected from following G2 group: Li Lalieting (linagliptin), sitagliptin (sitagliptin), vildagliptin (vildagliptin), A Gelieting (alogliptin), Sa Gelieting (saxagliptin), any one pharmaceutically acceptable salt in Na Lieting (denagliptin), Ka Gelieting (carmegliptin), MAG row spit of fland (melogliptin) and Du Gelieting (dutogliptin) or the above-mentioned DPPIV inhibitor, or its prodrug.
Term as used herein " Li Lalieting " is meant Li Lalieting and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.Crystal form is described among the WO 2007/128721.The method for preparing Li Lalieting for example is described among the patent application WO 2004/018468 and WO2006/048427.DPP IV inhibitor suitable on Li Lalieting and the structure is different; Because when itself and SGLT2 inhibitor of the present invention and the combination of the third antidiabetic drug are used, it merges special usefulness and long-acting and favourable pharmacological characteristics, receptor-selective and favourable side effect character or produces unexpected treatment advantage or improvement.
Term as used herein " sitagliptin " is meant sitagliptin (or MK-0431) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.In one embodiment, sitagliptin is its biphosphate salt form, i.e. sitagliptin phosphate.In another embodiment, sitagliptin phosphate is crystal anhydrous thing or monohydrate form.One type of this embodiment is meant the sitagliptin phosphate monohydrate.Januvia free base and pharmaceutically acceptable salt thereof are disclosed in United States Patent (USP) 6,699,871 and the embodiment 7 of WO 03/004498 in.Crystallization sitagliptin phosphate monohydrate is disclosed among WO2005/003135 and the WO 2007/050485.Therefore, about for example preparing or the details of the method for this compound or its salt of filling a prescription, with reference to these documents.Sitagliptin tablet formulations may be trade names
Figure BDA0000081995560000221
bought.
Term as used herein " vildagliptin " is meant vildagliptin (or LAF-237) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.The concrete salt of vildagliptin is disclosed among the WO 2007/019255.The crystal form of vildagliptin and vildagliptin tablet formulation are disclosed among the WO 2006/078593.Vildagliptin can be filled a prescription described in WO 00/34241 or WO 2005/067976.The vildagliptin preparation that improvement discharges is described among the WO 2006/135723.Therefore, about for example preparing or the details of the method for this compound or its salt of filling a prescription, with reference to these documents and US 6,166,063.The tablet formulation can be expected vildagliptin trade name bought.
Term as used herein " Sa Gelieting " is meant Sa Gelieting (or BMS-477118) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.In one embodiment, Sa Gelieting is free alkali or hydrochlorate (for example mono-hydrochloric salts or dihydrochloride comprise its hydrate) or single benzoate form, as disclosed among WO 2004/052850 and the WO 2008/131149.In another embodiment, Sa Gelieting is free alkali form.In another embodiment, Sa Gelieting is free alkali monohydrate form, as disclosed among the WO 2004/052850.The method for preparing Sa Gelieting also is disclosed among WO 2005/106011 and the WO 2005/115982.Sa Gelieting can fill a prescription into tablet, described in WO 2005/117841.Therefore, about for example preparing, fill a prescription or using the details of the method for this compound or its salt, with reference to these documents and United States Patent (USP) 6,395,767 and WO01/68603.
Term as used herein " Na Lieting " is meant ground Na Lieting (or GSK-823093) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.In one embodiment, ground Na Lieting is among the embodiment 2 of WO 03/002531 disclosed mesylate form among disclosed hydrochloride form or the WO2005/009956.One type of this embodiment is meant methanesulfonic acid ground Na Lieting.Crystal anhydrous methanesulfonic acid ground Na Lieting is disclosed among the WO 2005/009956.Therefore, about the details of the method for preparing this compound or its salt, with reference to these documents and United States Patent (USP) 7,132,443.
Term as used herein " A Gelieting " is meant A Gelieting (or SYR-322) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.In one embodiment, A Gelieting is benzoate, hydrochlorate or mesylate form, and each is as disclosed among the WO 2007/035629.One type of this embodiment is meant benzoic acid A Gelieting.The polymorphic of benzoic acid A Gelieting is disclosed among the WO 2007/035372.The method for preparing A Gelieting is disclosed among the WO 2007/112368, and especially is disclosed among the WO 2007/035629.A Gelieting (being its benzoate) can fill a prescription into tablet and administration described in WO2007/033266.Therefore, about for example preparing, fill a prescription or using the details of the method for this compound or its salt, with reference to these documents and US 2005/261271, EP1586571 and WO 2005/095381.
Term as used herein " Ka Gelieting " is meant Ka Gelieting and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.The method for preparing this chemical compound (especially its dihydrochloride) also is disclosed among WO 2008/031749, WO 2008/031750 and the WO 2008/055814.This chemical compound can be filled a prescription into pharmaceutical composition described in WO 2007/017423.Therefore, about for example preparing, fill a prescription or using the details of the method for this compound or its salt, with reference to these documents and WO2005/000848.
Term as used herein " MAG row spit of fland " is meant MAG row spit of fland and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.Its preparation method especially is disclosed among WO2006/040625 and the WO2008/001195.The salt of special demands protection comprises methane sulfonates and tosilate.Therefore, about for example preparing, fill a prescription or using the details of the method for this compound or its salt, with reference to these documents.
Term as used herein " Du Gelieting " is meant Du Gelieting (or PHX-1149, PHX-1149T) and pharmaceutically acceptable salt thereof, comprises its hydrate and solvate, and crystal form.Its preparation method especially is disclosed among the WO 2005/047297.Pharmaceutically acceptable salt comprises tartrate.Therefore, about for example preparing, fill a prescription or using the details of the method for this compound or its salt, with reference to these documents.
For avoiding any query, the disclosure of aforementioned each document of above quoting relevant with concrete DPP IV inhibitor is incorporated herein by reference with it in full.
The third antidiabetic drug is selected from following G3 group: biguanide, thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor, GLP-1 analog or its pharmaceutically acceptable salt.Preferred implementation about the third antidiabetic drug is hereinafter described.
The G3 group comprises biguanide.The instance of biguanide is metformin, phenformin (phenformin) and buformin (buformin).Preferred biguanide is a metformin.With the SGLT2 inhibitor and the DPPIV inhibitor of biguanide (especially metformin) combination more effective glycemic control can be provided; And can with the biguanide synergism for example reducing body weight, this produces comprehensive beneficial effect to the metabolism syndrome relevant with type ii diabetes usually.
Term as used herein " metformin " is meant metformin or its pharmaceutically acceptable salt; For example hydrochlorate, metformin (2: 1) fumarate and metformin (2: 1) succinate, hydrobromate, parachlorophen-oxyacetic acid salt or embonate (embonate), and the melbine salt of other known monobasic or dicarboxylic acids.The preferred Metformin of metformin used herein.
The G3 group comprises thiazolidinedione.The instance of thiazolidinedione (TZD) is pioglitazone (pioglitazone) and rosiglitazone (rosiglitazone).The TZD therapy is with significantly weight increase and fat distribute relevant again.In addition, TZD causes fluid retention and forbids in patients with congestive heart failure.Also increase relevant with the TZD long-term treatment with risk of bone fracture.The advantageous feature of SGLT2 inhibitor and DPPIV inhibitor (as reducing the ability of body weight) can make the side effect of TZD treatment reduce to minimum.
Term as used herein " pioglitazone " is meant pioglitazone, comprises its enantiomer, its mixture and racemic modification thereof, or its pharmaceutically acceptable salt, for example hydrochlorate.
Term as used herein " rosiglitazone " is meant rosiglitazone, comprises its enantiomer, its mixture and racemic modification thereof, or its pharmaceutically acceptable salt, for example maleate.
The G3 group comprises sulfonylureas.The instance of sulfonylureas is glibenclamide (glibenclamide), tolbutamide (tolbutamide), glimepiride (glimepiride), glipizide (glipizide), gliquidone (gliquidone), glibornuride (glibornuride), glibenclamide (glyburide), glisoxepide (glisoxepide) and gliclazide (gliclazide).Preferred sulfonylureas is tolbutamide, gliquidone, glibenclamide and glimepiride, especially glibenclamide and glimepiride.Because the effect of sulfonylureas exhausts with therapeutic process, so the combination of SGLT2 inhibitor and DPPIV inhibitor and sulfonylureas can provide added benefit to the patient with regard to better glycemic control.Equally, increase relevantly gradually with therapeutic process with body weight usually with sulfonylureas treatment, and the ability of SGLT2 inhibitor and DPPIV inhibitor reduction body weight can make this side effect of the treatment of sulfonylureas reduce to minimum and improve metabolism syndrome.This combination also can reduce sulfonylureas dosage, and wherein sulfonylureas possibly cause light hypoglycemia, and should light hypoglycemia be the unwanted side effect of sulfonylureas.
Each term that crowd as used herein " glibenclamide ", " glimepiride ", " gliquidone ", " glibornuride ", " gliclazide ", " glisoxepide ", " tolbutamide " reach " glipizide " is meant active medicine out of the ordinary or its pharmaceutically acceptable salt.
How the G3 group comprises row.Row instance how is Nateglinide (nateglinide), repaglinide (repaglinide) and Mitiglinide (mitiglinide).Because its effect exhausts with therapeutic process, so the combination of SGLT2 inhibitor and meglitinide (meglitinide) can provide added benefit to the patient with regard to better glycemic control.Equally, increase relevantly gradually with therapeutic process with body weight usually with meglitinide treatment, and the ability of SGLT2 inhibitor reduction body weight can make this side effect of the treatment of meglitinide reduce to minimum and improve metabolism syndrome.This combination also can reduce the dosage of meglitinide, and wherein meglitinide possibly cause light hypoglycemia, and should light hypoglycemia be the unwanted side effect of meglitinide.
Term as used herein " Nateglinide " is meant Nateglinide, comprises its enantiomer, its mixture and racemic modification thereof, or its pharmaceutically acceptable salt and ester.
Term as used herein " repaglinide " is meant repaglinide, comprises its enantiomer, its mixture and racemic modification thereof, or its pharmaceutically acceptable salt and ester.
The G3 group comprises alpha-glucosidase inhibitor.The instance of alpha-glucosidase inhibitor is acarbose (acarbose), voglibose (voglibose) and miglitol (miglitol).The additional benefit of the combination of SGLT2 inhibitor, DPPIV inhibitor and alpha-glucosidase inhibitor maybe be relevant with more effective glycemic control under the individual drug than low dosage, and this especially will reduce the unwanted the intestines and stomach side effect of alpha-glucosidase inhibitor.Additional benefit is: the whole body content that combination can produce whole body GLP-1 is higher than monotherapy out of the ordinary, and combination has the long-term benefit of expection to pancreas α cell and β cell.In addition, with glucose uptake and the combined comparable monotherapy out of the ordinary of homaluria that increases blood glucose more effectively blood sugar lowering, especially the GLPP peak value that suppress in the intestinal.Alpha-glucosidase inhibitor be not absorbed or systemic absorption extremely low, therefore and the removing of DPPIV and SGLT2 inhibitor is not disturbed in expection.
Each term that group as used herein " acarbose ", " voglibose " reach " miglitol " is meant active medicine out of the ordinary or its pharmaceutically acceptable salt.
The G3 group comprises the inhibitor of GLP-1 analog.The instance of GLP-1 analog is Exenatide (exenatide) and Li Lalu peptide (liraglutide).The combination of SGLT2 inhibitor, DPPIV inhibitor and GLP-1 analog can be in the glycemic control good than realization under the low dosage of individual drug.In addition, the body weight control potentiality of expection DPPIV inhibitor and SGLT2 inhibitor can further improve the ability that the GLP-1 analog reduces body weight.On the other hand, when combination DPP IV and SGLT2 inhibitor are used the GLP-1 analog of low dosage, can reduce side effect (for example feel sick, vomiting).
Each term that group as used herein " Exenatide " reaches " Li Lalu peptide " is meant active medicine out of the ordinary or its pharmaceutically acceptable salt.
In the first embodiment E1, pharmaceutical composition of the present invention, method and purposes preferably relate to the combination that SGLT2 inhibitor wherein is selected from the substituted benzene derivative of formula (I) glucopyranosyl,
Figure BDA0000081995560000261
R wherein 1, R 2And R 3Such as above definition.SGLT2 inhibitor even more preferably be selected from above defined chemical compound (I.1) to (I.11).According to first embodiment, SGLT2 inhibitor most preferred compound (I.9).
According to first embodiment, DPPIV inhibitor and the third antidiabetic drug preferably clauses and subclauses of table 1 are selected.
Table 1
Embodiment The DPPIV inhibitor The third antidiabetic drug
E1.1 Be selected from the G2 group Be selected from the G3 group
E1.2 Be selected from the G2 group Metformin
E1.3 Be selected from the G2 group Pioglitazone
E1.4 Be selected from the G2 group Rosiglitazone
E1.5 Be selected from the G2 group Glibenclamide
E1.6 Be selected from the G2 group Glimepiride
E1.7 Be selected from the G2 group Gliquidone
E1.8 Be selected from the G2 group Nateglinide
E1.9 Be selected from the G2 group Repaglinide
E1.10 Li Lalieting Be selected from the G3 group
E1.11 Li Lalieting Metformin
E1.12 Li Lalieting Pioglitazone
E1.13 Li Lalieting Rosiglitazone
E1.14 Li Lalieting Glibenclamide
E1.15 Li Lalieting Glimepiride
E1.16 Li Lalieting Gliquidone
E1.17 Li Lalieting Nateglinide
E1.18 Li Lalieting Repaglinide
E1.19 Sitagliptin Be selected from the G3 group
E1.20 Sitagliptin Metformin
E1.21 Sitagliptin Pioglitazone
E1.22 Sitagliptin Rosiglitazone
E1.23 Sitagliptin Glibenclamide
E1.24 Sitagliptin Glimepiride
E1.25 Sitagliptin Gliquidone
E1.26 Sitagliptin Nateglinide
E1.27 Sitagliptin Repaglinide
E1.28 Vildagliptin Be selected from the G3 group
E1.29 Vildagliptin Metformin
E1.30 Vildagliptin Pioglitazone
E1.31 Vildagliptin Rosiglitazone
E1.32 Vildagliptin Glibenclamide
E1.33 Vildagliptin Glimepiride
E1.34 Vildagliptin Gliquidone
E1.35 Vildagliptin Nateglinide
E1.36 Vildagliptin Repaglinide
E1.37 A Gelieting Be selected from the G3 group
E1.38 A Gelieting Metformin
E1.39 A Gelieting Pioglitazone
E1.40 A Gelieting Rosiglitazone
E1.41 A Gelieting Glibenclamide
E1.42 A Gelieting Glimepiride
E1.43 A Gelieting Gliquidone
E1.44 A Gelieting Nateglinide
E1.45 A Gelieting Repaglinide
E1.46 Sa Gelieting Be selected from the G3 group
E1.47 Sa Gelieting Metformin
E1.48 Sa Gelieting Pioglitazone
E1.49 Sa Gelieting Rosiglitazone
E1.50 Sa Gelieting Glibenclamide
E1.51 Sa Gelieting Glimepiride
E1.52 Sa Gelieting Gliquidone
E1.53 Sa Gelieting Nateglinide
E1.54 Sa Gelieting Repaglinide
E1.55 Ka Gelieting Be selected from the G3 group
E1.56 Ka Gelieting Metformin
E1.57 Ka Gelieting Pioglitazone
E1.58 Ka Gelieting Rosiglitazone
E1.59 Ka Gelieting Glibenclamide
E1.60 Ka Gelieting Glimepiride
E1.61 Ka Gelieting Gliquidone
E1.62 Ka Gelieting Nateglinide
E1.63 Ka Gelieting Repaglinide
E1.64 MAG row spit of fland Be selected from the G3 group
E1.65 MAG row spit of fland Metformin
E1.66 MAG row spit of fland Pioglitazone
E1.67 MAG row spit of fland Rosiglitazone
E1.68 MAG row spit of fland Glibenclamide
E1.69 MAG row spit of fland Glimepiride
E1.70 MAG row spit of fland Gliquidone
E1.71 MAG row spit of fland Nateglinide
E1.72 MAG row spit of fland Repaglinide
E1.73 Du Gelieting Be selected from the G3 group
E1.74 Du Gelieting Metformin
E1.75 Du Gelieting Pioglitazone
E1.76 Du Gelieting Rosiglitazone
E1.77 Du Gelieting Glibenclamide
E1.78 Du Gelieting Glimepiride
E1.79 Du Gelieting Gliquidone
E1.80 Du Gelieting Nateglinide
E1.81 Du Gelieting Repaglinide
In second embodiment E 2, pharmaceutical composition of the present invention, method and purposes preferably relate to the combination that the DPPIV inhibitor is Li Lalieting.According to second embodiment, SGLT2 inhibitor and the third antidiabetic drug are preferably selected according to the clauses and subclauses of table 2.
Table 2
Embodiment The SGLT2 inhibitor The third antidiabetic drug
E2.1 Be selected from the G1 group Be selected from the G3 group
E2.2 Be selected from the G1 group Metformin
E2.3 Be selected from the G1 group Pioglitazone
E2.4 Be selected from the G1 group Rosiglitazone
E2.5 Be selected from the G1 group Glibenclamide
E2.6 Be selected from the G1 group Glimepiride
E2.7 Be selected from the G1 group Gliquidone
E2.8 Be selected from the G1 group Nateglinide
E2.9 Be selected from the G1 group Repaglinide
E2.10 Chemical compound (I.9) Be selected from the G3 group
E2.11 Chemical compound (I.9) Metformin
E2.12 Chemical compound (I.9) Pioglitazone
E2.13 Chemical compound (I.9) Rosiglitazone
E2.14 Chemical compound (I.9) Glibenclamide
E2.15 Chemical compound (I.9) Glimepiride
E2.16 Chemical compound (I.9) Gliquidone
E2.17 Chemical compound (I.9) Nateglinide
E2.18 Chemical compound (I.9) Repaglinide
E2.19 Da Gelie is clean Be selected from the G3 group
E2.20 Da Gelie is clean Metformin
E2.21 Da Gelie is clean Pioglitazone
E2.22 Da Gelie is clean Rosiglitazone
E2.23 Da Gelie is clean Glibenclamide
E2.24 Da Gelie is clean Glimepiride
E2.25 Da Gelie is clean Gliquidone
E2.26 Da Gelie is clean Nateglinide
E2.27 Da Gelie is clean Repaglinide
E2.28 Kan Gelie is clean Be selected from the G3 group
E2.29 Kan Gelie is clean Metformin
E2.30 Kan Gelie is clean Pioglitazone
E2.31 Kan Gelie is clean Rosiglitazone
E2.32 Kan Gelie is clean Glibenclamide
E2.33 Kan Gelie is clean Glimepiride
E2.34 Kan Gelie is clean Gliquidone
E2.35 Kan Gelie is clean Nateglinide
E2.36 Kan Gelie is clean Repaglinide
E2.37 A Gelie is clean Be selected from the G3 group
E2.38 A Gelie is clean Metformin
E2.39 A Gelie is clean Pioglitazone
E2.40 A Gelie is clean Rosiglitazone
E2.41 A Gelie is clean Glibenclamide
E2.42 A Gelie is clean Glimepiride
E2.43 A Gelie is clean Gliquidone
E2.44 A Gelie is clean Nateglinide
E2.45 A Gelie is clean Repaglinide
E2.46 Rui Gelie is clean Be selected from the G3 group
E2.47 Rui Gelie is clean Metformin
E2.48 Rui Gelie is clean Pioglitazone
E2.49 Rui Gelie is clean Rosiglitazone
E2.50 Rui Gelie is clean Glibenclamide
E2.51 Rui Gelie is clean Glimepiride
E2.52 Rui Gelie is clean Gliquidone
E2.53 Rui Gelie is clean Nateglinide
E2.54 Rui Gelie is clean Repaglinide
E2.55 She Gelie is clean Be selected from the G3 group
E2.56 She Gelie is clean Metformin
E2.57 She Gelie is clean Pioglitazone
E2.58 She Gelie is clean Rosiglitazone
E2.59 She Gelie is clean Glibenclamide
E2.60 She Gelie is clean Glimepiride
E2.61 She Gelie is clean Gliquidone
E2.62 She Gelie is clean Nateglinide
E2.63 She Gelie is clean Repaglinide
During listed the present invention makes up in table 1 and table 2, even more preferably make up E1.1 to E1.18 and E2.1 to E2.18, especially E1.10 to E1.18 and E2.10 to E2.18, especially E1.11 to E2.11.
Compare with the monotherapy (for example metformin monotherapy) that uses independent SGLT2 inhibitor or DPP IV inhibitor or the third antidiabetic drug; The combination of SGLT2 inhibitor of the present invention, DPPIV inhibitor and the third antidiabetic drug significantly improves glycemic control, especially hereinafter described patient's glycemic control.In addition; With use SGLT2 inhibitor and DPP IV inhibitor; Or use SGLT2 inhibitor and the third antidiabetic drug; Or use the combination treatment of DPPIV inhibitor and the third antidiabetic drug to compare; The combination of SGLT2 inhibitor of the present invention, DPPIV inhibitor and the third antidiabetic drug improves glycemic control, especially hereinafter described patient's glycemic control.The glycemic control improvement is defined as blood glucose and reduces increase and HbAlc minimizing increase.For the monotherapy among the patient (patient especially hereinafter described), generally can not further improve glycemic control significantly through the medicine that is higher than specific maximum dose level.In addition, in view of potential side effect, possibly not expect the treatment of life-time service maximum dose level.Therefore, can not in all patients, reach gratifying glycemic control through the monotherapy that uses independent SLGT2 inhibitor or DPP IV inhibitor or the third antidiabetic drug.Even only use two kinds of combination treatments that are selected from the medicine of SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug can't in all patients, produce complete glycemic control and/or produce complete glycemic control for a long time.In these patients, diabetes possibly continue progress and possibly occur and the diabetes complications associated with arterial system, for example the trunk complication.With corresponding monotherapy or only use the therapy of two kinds of combination collocation things to compare; Pharmaceutical composition of the present invention and the inventive method make more patients' HbAlc value be reduced to required target zone; For example＜7% and preferred＜6.5%, and the therapeutic treatment time is longer.
In addition, the combination of SGLT2 inhibitor of the present invention, DPP IV inhibitor and the 3rd therapeutic agent allow to reduce SGLT2 inhibitor, DPP IV inhibitor or the third antidiabetic drug or even the dosage of two or three active ingredient.It is useful to the patient that dosage reduces, otherwise it possibly used side effect, the especially side effect that causes of the third antidiabetic drug of therapy of one or more active ingredients of higher dosage.Therefore therefore, pharmaceutical composition of the present invention and the inventive method show less side effect, therapy are more tolerated and improve the compliance of patient to treatment.
Use the monotherapy of DPP IV inhibitor or use the combination treatment of DPPIV inhibitor of the present invention and the third antidiabetic drug relevant with patient's insulin secretion ability or insulin sensitivity.On the other hand, it is irrelevant to give SGLT2 inhibitor for treating of the present invention and patient's insulin secretion ability or insulin sensitivity.Therefore, any patient all can with the irrelevant situation of hyperinsulinism content or insulin resistance and/or hyperinsulinemia under benefit from the therapy of the combination of using SGLT2 inhibitor of the present invention and DPPIV inhibitor and the third antidiabetic drug.Because combination or alternately give the SGLT2 inhibitor, thus these patients still can with the irrelevant situation of hyperinsulinism content or insulin resistance or hyperinsulinemia under with the combined therapy of DPP IV inhibitor and the third antidiabetic drug.
Through improving active GLP-1 content, DPP IV inhibitor of the present invention can reduce patient's glucagon secretion.Therefore, this will limit the hepatic glucose generation.In addition, the high activity GLP-1 content of DPP IV inhibitor generation will be to β cell regeneration and the newborn beneficial effect that produces.All these characteristics of DPP IV inhibitor make with the combination of SGLT2 inhibitor and quite are suitable for and tool important meaning in treatment.
When the present invention mentioned the patient who needs treatment or prevention, it mainly referred to people's treatment and prevention, but pharmaceutical composition also can be applied in the mammiferous veterinary mutually.In the scope of the invention, the adult patient preferred age is 18 years old or above people.In the scope of the invention, the patient is a teenager equally, and promptly the age is that 10 to 17 years old, preferred age are 13 to 17 years old people.Think in teenager colony, give pharmaceutical composition of the present invention, can find that splendid HbAlc reduces and splendid fasting plasma glucose reduces.In addition, think in teenager colony, especially in overweight and/or obese patient, can be observed remarkable body weight and reduce.
As indicated above, through giving pharmaceutical composition of the present invention, and especially since wherein the high SGLT2 of SGLT2 inhibitor suppress active, excess blood glucose is discharged through patient's urine, make body weight not increase or even body weight reduce.Therefore; Treatment of the present invention or prevention needing advantageously to be suitable for the patient of this treatment or prevention; These patients have one or more after diagnosing and are selected from following disease: overweight and obesity, especially I level obesity, II level obesity, III level obesity, visceral obesity and abdominal fatness.In addition, treatment of the present invention or the prevention advantageously be suitable for avoiding weight increase the patient.For example owing to give the third antidiabetic drug, therefore the effect of any weight increase of therapy possibly weaken or even eliminate.
Pharmaceutical composition of the present invention and especially wherein SGLT2 inhibitor show splendid glycemic control effect, especially reduce the fasting plasma glucose, after the meal aspect plasma glucose and/or the glycosylated hemoglobin (HbAlc).Through giving pharmaceutical composition of the present invention, accessible HbAlc reduces and is equal to or greater than preferably 1.0%, more preferably is equal to or greater than 2.0%, even more preferably is equal to or greater than 3.0%, and reduce especially in 1.0% to 3.0% scope.
In addition, method of the present invention and/or purposes are advantageously used in and show patients a kind of, two or more following diseases:
(a) fasting glucose or serum glucose concentration are greater than 100mg/dL or 110mg/dL, especially greater than 125mg/dL;
(b) plasma glucose is equal to or greater than 140mg/dL after the meal;
(c) the HbAlc value is equal to or greater than 6.5%, especially is equal to or greater than 7.0%, especially is equal to or greater than 7.5%, even more specifically is equal to or greater than 8.0%.
The present invention also discloses the purposes of pharmaceutical composition in the patient's who is used for improving first symptom of suffering from type ii diabetes or demonstration pre-diabetes glycemic control.Therefore, the present invention also comprises diabetes mellitus prevention.Therefore, if after above-mentioned a kind of pre-diabetes symptom occurs, promptly use pharmaceutical composition of the present invention to improve glycemic control, then can postpone or prevent the outbreak of dominance type ii diabetes.
In addition; Pharmaceutical composition of the present invention is particularly suited for treating the patient with insulin-dependent, promptly through insulin or insulin derivates or insulin substitution thing or comprise the preparation for treating of insulin or derivatives thereof or substitute or will or need the patient of its treatment through its treatment.These patients comprise type ii diabetes patient and type i diabetes patient.
Therefore; According to a preferred implementation of the present invention; In the patient who needs is arranged, provide and improve glycemic control and/or reduce fasting plasma glucose, the method for plasma glucose and/or glycosylation hematochrome HbAlc after the meal; This patient suffers from glucose tolerance after diagnosing and reduces (IGT), impaired fasting glucose (IFG), insulin resistance, metabolism syndrome and/or II type or type i diabetes, and the SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug (for example) that the method is characterized in that contextual definition are to make up or alternately to give the patient.
According to another preferred implementation of the present invention, provide and improve type ii diabetes patient, the method for the glycemic control of adult patient especially as the supplementary means of diet and motion.
Can find; The pharmaceutical composition of the application of the invention; Even in the inadequate patient of glycemic control; Although although especially through antidiabetic drug treatment, for example through the combination of metformin, SGLT2 inhibitor or the oral monotherapy of DPPIV inhibitor of maximum recommended or tolerance dose or metformin and SGLT2 inhibitor or the combination of metformin and DPPIV inhibitor, SGLT2 inhibitor especially of the present invention or DPP IV inhibitor for treating of the present invention but among the still inadequate patient of glycemic control, also can reach the improvement of glycemic control.The maximum recommended of metformin or tolerance dose are 2000mg every day for example, or 1500mg every day (for example in Asian countries) or every day three 850mg or its any equivalent.SGLT2 inhibitor of the present invention, especially maximum recommended or the tolerance dose of chemical compound (I.9) are for example 100mg or 50mg or even 25mg or 10mg or its any equivalent once a day.The maximum recommended of Li Lalieting or tolerance dose are for example 10mg once a day, preferred 5mg or its any equivalent.The maximum recommended of sitagliptin or tolerance dose are for example 100mg or its any equivalent once a day.
Therefore, method of the present invention and/or purposes are advantageously used in and show patients a kind of, two or more following diseases:
(a) use independent diet and motion and glycemic control is insufficient;
(b) although carried out the oral monotherapy of metformin, although carried out the oral monotherapy of the metformin of maximum recommended or tolerance dose especially, glycemic control is still insufficient;
(c) although carried out the oral monotherapy of the third antidiabetic drug, although carried out the oral monotherapy of the third antidiabetic drug of maximum recommended or tolerance dose especially, glycemic control is still insufficient;
(d) although carried out the oral monotherapy of SGLT2 inhibitor, although carried out the oral monotherapy of the SGLT2 inhibitor of maximum recommended or tolerance dose especially, glycemic control is still insufficient;
(e) although carried out the oral monotherapy of DPPIV inhibitor, although carried out the oral monotherapy of the DPPIV inhibitor of maximum recommended or tolerance dose especially, glycemic control is still insufficient;
(f) although carried out the combination treatment of the medicine of two kinds of groups that are selected from SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug, glycemic control is still insufficient;
(g) although carried out the oral combination treatment of SGLT2 inhibitor and the third antidiabetic drug (for example metformin); Although carried out the oral monotherapy of at least a composition of medicine (combination partner) of maximum recommended or tolerance dose especially, glycemic control is still insufficient;
(h) although carried out the oral combination treatment of DPPIV inhibitor and the third antidiabetic drug (for example metformin), although carried out the oral monotherapy of at least a combination collocation thing of maximum recommended or tolerance dose especially, glycemic control is still insufficient.
Blood sugar content through giving due to the SGLT2 inhibitor of the present invention reduces with insulin irrelevant.Therefore, pharmaceutical composition of the present invention is particularly suited for treating the patient who suffers from one or more following diseases after diagnosing:
-insulin resistance,
-hyperinsulinemia,
-pre-diabetes,
-type ii diabetes, especially late period type ii diabetes,
-type i diabetes.
In addition, pharmaceutical composition of the present invention is particularly suited for treating the patient who suffers from one or more following diseases after diagnosing:
(a) obesity (comprising I level, II level and/or III level obesity), visceral obesity and/or abdominal fatness,
(b) triglyceride blood content >=150mg/dL,
(c) female patient HDL-cholesteremia liquid hold-up＜40mg/dL and male patient＜50mg/dL,
(d) systolic pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting glucose content >=100mg/dL.
Think that suffering from patient that glucose tolerance reduces (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolism syndrome after diagnosing develops the risk of cardiovascular disease (for example myocardial infarction, coronary heart disease, cardiac dysfunction, thromboembolic events) and increase.Glycemic control of the present invention can make cardiovascular risk reduce.
In addition, pharmaceutical composition of the present invention and method are particularly suited for treating the patient after the organ transplantation, especially the patient of diagnosis with one or more following diseases:
(a) age higher, especially be higher than 50 years old,
(b) male gender,
(c) overweight, obesity (comprising I level, II level and/or III level obesity), visceral obesity and/or abdominal fatness,
(d) transplant preceding diabetes,
(e) immunosuppressive therapy.
In addition, pharmaceutical composition of the present invention and method are particularly suited for treating the patient who suffers from one or more following diseases after diagnosing:
(a) hyponatremia, especially chronic hyponatremia;
(b) water intoxication;
(c) water retention;
(d) plasma sodium concentration is lower than 135mmol/L.
The patient can be diabetes mammal or non-diabetic mammal, especially people.
In addition, pharmaceutical composition of the present invention and method are particularly suited for treating the patient who suffers from one or more following diseases after diagnosing:
(a) high serum uric acid content is especially greater than 6.0mg/dL (357 μ mol/L);
(b) gouty arthritis medical history, especially recurrent gout arthritis;
(c) renal calculus, especially recurrent renal calculus;
(d) the high trend of formation renal calculus.
Pharmaceutical composition of the present invention especially owing to wherein SGLT2 inhibitor and DPPIV inhibitor, shows good safety character.Therefore, treatment of the present invention or prevention are used the monotherapy of another antidiabetic drug (for example metformin) to taboo and/or patient that these medicines of therapeutic dose are not tolerated maybe be favourable.Treatment of the present invention or prevention especially maybe be favourable to showing one or more following diseases or having the patient of one or more following diseases that risk increases: the catabolism state of renal insufficiency or nephropathy, heart disease, heart failure, hepatopathy, pneumonopathy, lactic acidosis (catabolytic state) and/or dangerous or period of pregnancy or breast-feeding female patient.
In addition, find to give that pharmaceutical composition of the present invention does not have the hypoglycemia risk or the hypoglycemia risk is low.Therefore, treatment of the present invention or prevention also maybe be favourable to the patient of the risk increase of demonstration hypoglycemia or trouble hypoglycemia.
Pharmaceutical composition of the present invention is particularly suited for being particularly suited for its long-term glycemic control in the medium-term and long-term treatment of type ii diabetes patient or prevention described disease of context and/or disease.
The term used like context " for a long time " expression was longer than for 12 weeks to patient's treatment or to patient's time of administration, preferably was longer than for 25 weeks, even more preferably was longer than 1 year.
Therefore, of the present invention one especially preferred implementation provide and improve (improving especially for a long time) type ii diabetes patient, especially late period the type ii diabetes patient, especially also suffer from the patient's of overweight, obesity (comprising I level, II level and/or III level obesity), visceral obesity and/or abdominal fatness the Therapeutic Method (preferred oral therapy) of glycemic control after diagnosing.
When SGLT2 inhibitor, DPP IV inhibitor and the third antidiabetic drug give (for example giving simultaneously with single preparation or with two or three other preparations of branch) with combination and when it alternately gives (for example giving successively with two or three other preparations of branch), all observe above-mentioned effect.
Be to be understood that; Desire to the patient give and the amount of the pharmaceutical composition of the present invention that in the present invention treatment or prevention, needs to use will be with route of administration, need character and the order of severity, patient age, body weight and the health of the disease of treatment or prevention, concomitant drugs to change, and determine by resident doctor (attendant physician) the most at last.Yet generally speaking, the amount of included SGLT2 inhibitor of the present invention, DPP IV inhibitor and the third antidiabetic drug is enough in its combination and/or improves the glycemic control of waiting to treat the patient when alternately giving in pharmaceutical composition or the dosage form.
In order to treat hyperuricemia or hyperuricemia associated conditions, the amount of included SGLT2 inhibitor of the present invention is enough to treat hyperuricemia and the plasma glucose stable state of not disturbing the patient in pharmaceutical composition or the dosage form, does not especially bring out hypoglycemia.
In order to treat or prevent renal calculus, the amount of included SGLT2 inhibitor of the present invention is enough to treat or prevents renal calculus and do not disturb patient's plasma glucose stable state in pharmaceutical composition or the dosage form, does not especially bring out hypoglycemia.
In order to treat hyponatremia and associated conditions, the amount of included SGLT2 inhibitor of the present invention is enough to treat hyponatremia or associated conditions and does not disturb patient's plasma glucose stable state in pharmaceutical composition or the dosage form, does not especially bring out hypoglycemia.
The preferable range of the amount of desire adopts in pharmaceutical composition of the present invention and the inventive method and the purposes SGLT2 inhibitor, DPP IV inhibitor and the third antidiabetic drug is hereinafter described.These scopes are meant the amount that gives every day with regard to adult patient (especially for example body weight is the people of about 70kg) and can be according to giving to reach other route of administration more than 2,3,4 times or 4 times every day and patient age is corresponding adjusts.The scope of dosage and amount is calculated to indivedual active parts.Employed indivedual SGLT2 inhibitor in the combination treatment of the present invention, indivedual DPP IV inhibitor and/or individually the dosage of the third antidiabetic drug should be lower than monotherapy or know employed dosage in the therapy, thereby the possible toxicity and the adverse side effect that cause when avoiding those medicines as monotherapy.
Within the scope of the present invention, the pharmaceutical composition preferred oral gives.Other form of medication also maybe and be described in hereinafter.The dosage form that one or more dosage forms that comprise SGLT2 inhibitor, DPPIV inhibitor and/or the third antidiabetic drug are preferably peroral dosage form or generally know.
Generally speaking, the amount of the SGLT2 inhibitor of pharmaceutical composition of the present invention and method is preferably in 1/5 to 1/1 scope of general amount of recommending to the monotherapy that uses this SGLT2 inhibitor.
The preferred dose scope of SGLT2 inhibitor is 0.5mg to 200mg every day, even more preferably every day 1, most preferably every day 1 was to 50mg to 100mg.The preferred oral administration.Therefore, pharmaceutical composition can comprise amount mentioned above, and especially 1 to 50mg or 1 to 25mg.Concrete dosage specification (for example every tablet or capsule) is for example 1,2.5,5,7.5,10,12.5,15,20,25 or 50mg formula (I) chemical compound, and especially chemical compound (I.9) or Da Gelie are clean.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.
Generally speaking, the amount of the DPP IV inhibitor of pharmaceutical composition of the present invention and method is preferably in 1/5 to 1/1 scope of general amount of recommending to the monotherapy that uses this DPP IV inhibitor.
During orally give, the preferred dose scope of Li Lalieting is 0.5mg to 10mg every day, preferred every day 2.5mg to 10mg, most preferably every day 1mg to 5mg.The preferable range of the amount in the pharmaceutical composition is 0.5 to 10mg, and especially 1 to 5mg.The instance of concrete dosage specification is 1,2.5,5 or 10mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.The Li Lalieting preparation that is fit to can be disclosed those preparations among the application WO 2007/128724, and the disclosure of this application is incorporated herein by reference it in full.
During orally give, the preferred dose scope of sitagliptin be every day 10 to 200mg, especially every day 25 is to 150mg.The recommended dose of sitagliptin with active part (free alkali anhydride) be calculated as once a day 100mg or every day twice 50mg.The preferable range of the amount in the pharmaceutical composition is 10 to 150mg, especially is 25 to 100mg.Instance is 25,50,75 or 100mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.Salt that can corresponding calculating sitagliptin, the equivalent of phosphate monohydrate especially.Chronic renal failure patients is preferably used the sitagliptin of adjustment dosage, and for example 25 and 50mg.
During orally give, the preferred dose scope of vildagliptin be every day 10 to 150mg, especially every day 25 to 150mg, 25 to 100mg or 25 to 50mg or 50 is to 100mg.For example, administration every day of vildagliptin is 50 or 100mg.The preferable range of the amount in the pharmaceutical composition is 10 to 150mg, and especially 25 to 100mg.Instance is 25,50,75 or 100mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.
During orally give, the preferred dose scope of A Gelieting be every day 5 to 250mg, especially every day 10 is to 150mg.The preferable range of the amount in the pharmaceutical composition is 5 to 150mg, and especially 10 to 100mg.Instance is 10,12.5,20,25,50,75 and 100mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.
During orally give, the preferred dose scope of Sa Gelieting be every day 2.5 to 100mg, especially every day 2.5 is to 50mg.The preferable range of the amount in the pharmaceutical composition is 2.5 to 100mg, and especially 2.5 to 50mg.Instance is 2.5,5,10,15,20,30,40,50 and 100mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.
During orally give, the preferred dose scope of Du Gelieting be every day 50 to 400mg, especially every day 100 is to 400mg.The preferable range of the amount in the pharmaceutical composition is 50 to 400mg.Instance is 50,100,200,300 and 400mg.But using of active ingredient reaches 3 every day, preferred every day 1 or 2 times.
Generally speaking, the amount of the third antidiabetic drug of pharmaceutical composition of the present invention and method is preferably in 1/5 to 1/1 scope of general amount of recommending to the monotherapy that uses this antidiabetic drug.Use is lower than indivedual the third antidiabetic drugs of the dosage of monotherapy can avoid or minimize possible toxicity and the adverse side effect that when those medicines are used as monotherapy, causes.
During orally give, the preferred dose scope of metformin be every day 250 to 3000mg, especially every day 500 is to 2000mg.The preferable range of the amount in the pharmaceutical composition should be 250 mutually to 1000mg, and especially 500 to 1000mg or 250 to 850mg.Instance is 500,750,850 or 1000mg.Being preferably once a day of this tittle, twice of every day or every day three times.For example, 500,750 and the amount of 850mg preferably needs once a day, twice of every day or three administrations every day, and the amount of 1000mg preferably needs once a day or twice administration every day.Some controlled release or extended release preparation allow administration once a day.Metformin can for example be with trade mark GLUCOPHAGE TM, GLUCOPHAGE-D TMOr GLUCOPHAGE-XR TMThe sale form give.
During orally give, the preferred dose scope of pioglitazone is that every day 5 is to 50mg.The preferable range of the amount in the pharmaceutical composition is corresponding to be respectively 5 to 50mg, 10 to 45mg and 15 to 45mg.Instance is 15,30 or 45mg.Being preferably once a day or every day twice of this tittle is especially for once a day.Pioglitazone can be with for example trade mark ACTOS TMThe sale form give.
During orally give, the preferred dose scope of rosiglitazone is 1mg to 10mg every day.The preferable range of the amount in the pharmaceutical composition is 1 to 10mg, 2 to 8mg, 4 to 8mg and 1 to 4mg.Instance is 1,2,4 or 8mg.Being preferably once a day or twice of every day of this tittle.Dosage preferably should be no more than 8mg every day.Rosiglitazone can be with for example trade mark AVANDIA TMThe sale form give.
During orally give, the preferred dose scope of thiazolidinedione (except that pioglitazone as indicated above or the rosiglitazone) is that every day 2 is to 100mg.Give every day once, the preferable range of the amount of the pharmaceutical composition of twice or three times is respectively 2 to 100mg, 1 to 50mg and 1 to 33mg.
During orally give, the preferred dose scope of glibenclamide be every day 0.5 to 15mg, especially every day 1 is to 10mg.The preferable range of the amount in the pharmaceutical composition is 0.5 to 5mg, and especially 1 to 4mg.Instance is 1.0,1.75 and 3.5mg.Being preferably once a day of this tittle, twice of every day or every day three times.Glibenclamide can be with for example trade mark EUGLUCON TMThe sale form give.
During orally give, the preferred dose scope of glimepiride be every day 0.5 to 10mg, especially every day 1 is to 6mg.The preferable range of the amount in the pharmaceutical composition is 0.5 to 10mg, and especially 1 to 6mg.Instance is 1,2,3,4 and 6mg.Being preferably once a day of this tittle, twice of every day or every day three times, preferably once a day.Glimepiride can be with for example trade mark AMARYL TMThe sale form give.
During orally give, the preferred dose scope of gliquidone be every day 5 to 150mg, especially every day 15 is to 120mg.The preferable range of the amount in the pharmaceutical composition is 5 to 120mg, and especially 5 to 30mg.Instance is 10,20,30mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.Gliquidone can be with for example trade mark GLURENORM TMThe sale form give.
During orally give, the preferred dose scope of glibornuride is that every day 5 is to 75mg.The preferable range of the amount in the pharmaceutical composition is 5 to 75mg, and especially 10 to 50mg.Being preferably once a day of this tittle, twice of every day or every day three times.
During orally give, the preferred dose scope of gliclazide be every day 20 to 300mg, especially every day 40 is to 240mg.The preferable range of the amount in the pharmaceutical composition is 20 to 240mg, and especially 20 to 80mg.Instance is 20,30,40 and 50mg.Being preferably once a day of this tittle, twice of every day or every day three times.
During orally give, the preferred dose scope of glisoxepide be every day 1 to 20mg, especially every day 1 is to 16mg.The preferable range of the amount in the pharmaceutical composition is 1 to 8mg, and especially 1 to 4mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.
During orally give, the preferred dose scope of tolbutamide be every day 100 to 3000mg, preferred every day 500 is to 2000mg.The preferable range of the amount in the pharmaceutical composition is 100 to 1000mg.Being preferably once a day or twice of every day of this tittle.
During orally give, the preferred dose scope of glipizide be every day 1 to 50mg, especially every day 2.5 is to 40mg.Give every day once, the preferable range of the amount of the pharmaceutical composition of twice or three times is respectively 1 to 50mg, 0.5 to 25mg and 0.3 to 17mg.
During orally give, the preferred dose scope of Nateglinide be every day 30 to 500mg, especially every day 60 is to 360mg.The preferable range of the amount in the pharmaceutical composition is 30 to 120mg.Instance is 30,60 and 120mg.Being preferably once a day of this tittle, twice of every day or every day three times.Nateglinide can be with for example trade mark STARLIX TMThe sale form give.
During orally give, the preferred dose scope of repaglinide be every day 0.1 to 16mg, especially every day 0.5 is to 6mg.The preferable range of the amount in the pharmaceutical composition is 0.5 to 4mg.Instance is 0.5,1,2 or 4mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.Repaglinide can be with for example trade mark NOVONORM TMThe sale form give.
During orally give, the preferred dose scope of acarbose be every day 50 to 1000mg, especially every day 50 is to 600mg.The preferable range of the amount in the pharmaceutical composition is 50 to 150mg.Instance is 50 and 100mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.Acarbose can be with for example trade mark Glucobay TMThe sale form give.
During orally give, the preferred dose scope of voglibose be every day 100 to 1000mg, especially every day 200 is to 600mg.The preferable range of the amount in the pharmaceutical composition is 50 to 300mg.Instance is 50,100,150,200 and 300mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.Voglibose can be with for example trade mark Basen TMOr Voglisan TMThe sale form give.
During orally give, the preferred dose scope of miglitol be every day 25 to 500mg, especially every day 25 is to 300mg.The preferable range of the amount in the pharmaceutical composition is 25 to 100mg.Instance is 25,50 and 100mg.Being preferably once a day of this tittle, twice of every day, every day three times or every day four times.Miglitol can be with for example trade mark Glyset TMThe sale form give.
The preferred dose scope of GLP-1 analog (especially Exenatide) is μ g every days 5 to 30, especially every days 5 to 20 μ g.The preferable range of the amount in the pharmaceutical composition is 5 to 10 μ g.Instance is 5 and 10 μ g.Being preferably once a day of this tittle, twice of every day, every day three times or every day four subcutaneous injections.Exenatide can be with for example trade mark Byetta TMThe sale form give.Durative action preparation (being preferred for weekly subcutaneous injection) comprises 0.1 to 3.0mg, the Exenatide of preferred 0.5 to 2.0mg amount.Instance is 0.8mg and 2.0mg.The instance of Exenatide durative action preparation is Byetta LAR TM
The preferred dose scope of Li Lalu peptide be every day 0.5 to 3mg, especially every day 0.5 is to 2mg.The preferable range of the amount in the pharmaceutical composition is 0.5 to 2mg.Instance is 0.6,1.2 and 1.8mg.This tittle be preferably once a day or every day twice subcutaneous injection.
The amount of the SGLT2 inhibitor in pharmaceutical composition of the present invention and the inventive method and the purposes, DPP IV inhibitor and the 3rd therapeutic agent is corresponding to dosage range out of the ordinary provided above.For example, the preferred dose scope in pharmaceutical composition of the present invention and the inventive method and the purposes is the SGLT2 inhibitor of formula (I) of the amount of 1 to 50mg (especially 1 to 25mg), especially chemical compound (I.9); 0.5 metformin to the amount of the Li Lalieting and 250 to 1000mg (especially 250 to 850mg) of the amount of 10mg (especially 1 to 5mg).Preferred every day orally give once or twice.
Another instance of preferred dose scope in pharmaceutical composition of the present invention or the inventive method or the purposes is the SGLT2 inhibitor of formula (I) of the amount of 1 to 50mg (especially 1 to 25mg), especially chemical compound (I.9); 0.5 pioglitazone to the amount of the Li Lalieting and 5 to 50mg (especially 10 to 45mg) of the amount of 10mg (especially 1 to 5mg).Preferred every day orally give once.
Another instance of preferred dose scope in pharmaceutical composition of the present invention or the inventive method or the purposes is that the Da Gelie of amount of 1 to 50mg (especially 1 to 25mg) is clean; 0.5 metformin to the amount of the Li Lalieting and 250 to 1000mg (especially 250 to 850mg) of the amount of 10mg (especially 1 to 5mg).Preferred every day orally give once or twice.
Another instance of preferred dose scope in pharmaceutical composition of the present invention or the inventive method or the purposes is the SGLT2 inhibitor of formula (I) of the amount of 1 to 50mg (especially 1 to 25mg), especially chemical compound (I.9); The metformin of the amount of the vildagliptin of the amount of 10 to 150mg (especially 25 to 100mg) and 250 to 1000mg (especially 250 to 850mg).Preferred every day orally give once or twice.
Another instance of preferred dose scope in pharmaceutical composition of the present invention or the inventive method or the purposes is the SGLT2 inhibitor of formula (I) of the amount of 1 to 50mg (especially 1 to 25mg), especially chemical compound (I.9); The metformin of the amount of the A Gelieting of the amount of 5 to 150mg (especially 10 to 100mg) and 250 to 1000mg (especially 250 to 850mg).Preferred every day orally give once or twice.
Another instance of preferred dose scope in pharmaceutical composition of the present invention or the inventive method or the purposes is the SGLT2 inhibitor of formula (I) of the amount of 1 to 50mg (especially 1 to 25mg), especially chemical compound (I.9); 2.5 metformin to the amount of the Sa Gelieting and 250 to 1000mg (especially 250 to 850mg) of the amount of 100mg (especially 2.5 to 50mg).Preferred every day orally give once or twice.
In the inventive method and purposes, SGLT2 inhibitor and DPP IV inhibitor and the 3rd therapeutic agent give or alternately give with combination.Term " combination gives " is meant that (promptly simultaneously) or same basically time give active ingredient at one time.Term " alternately gives " to be meant and at first gives one or both active ingredients, and after a period of time, gives other two kinds or a kind of active ingredient, promptly gives at least two kinds in three kinds of active ingredients successively.This a period of time can be in 30 minutes to 12 hours scopes.Combination or alternately can be once a day, twice of every day, every day three times or every day four times, preferably once a day or twice.
About giving of SGLT2 inhibitor and DPP IV inhibitor and the third antidiabetic drug; All three kinds of active ingredients can be present in the single dosage form; For example in tablet or the capsule, or one or two kind of active ingredient can be present in other dosage form of branch, for example in two similar and different dosage forms.
About alternately giving, one or two kind of active ingredient be present in other dosage form of branch, for example in two similar and different dosage forms.
Therefore, pharmaceutical composition of the present invention can be the single dosage form that comprises SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug.Perhaps; Pharmaceutical composition of the present invention can be two other dosage forms of branch; One of them dosage form comprises SGLT2 inhibitor and another dosage form and comprises DPP IV inhibitor and add the third antidiabetic drug, or a dosage form comprises, and the SGLT2 inhibitor adds the third antidiabetic drug and another dosage form comprises DPP IV inhibitor.Perhaps, pharmaceutical composition of the present invention can be three other dosage forms of branch, and one of them dosage form comprises the SGLT2 inhibitor and second dosage form comprises DPP IV inhibitor and the 3rd dosage form comprises the third antidiabetic drug.
Therefore, according to an embodiment, pharmaceutical composition of the present invention is characterised in that SGLT2 inhibitor and DPP IV inhibitor are present in the single dosage form and the third antidiabetic drug is present in other dosage form of branch.
According to another embodiment, pharmaceutical composition of the present invention is characterised in that SGLT2 inhibitor and the third antidiabetic drug are present in the single dosage form and DPP IV inhibitor is present in other dosage form of branch.
According to another embodiment, pharmaceutical composition of the present invention is characterised in that DPPIV inhibitor and the third antidiabetic drug are present in the single dosage form and the SGLT2 inhibitor is present in other dosage form of branch.
According to another embodiment, pharmaceutical composition of the present invention is characterised in that SGLT2 inhibitor, DPP IV inhibitor and the third antidiabetic drug are present in the single dosage form.
According to another embodiment, pharmaceutical composition of the present invention is characterised in that SGLT2 inhibitor, DPP IV inhibitor and the third antidiabetic drug respectively are present in other dosage form of branch.
This situation possibly appear when a kind of active ingredient must more frequently give (for example every day twice) than another active ingredient (for example need give once a day).Therefore, term " combination or alternately give " also comprises at first combination or alternately gives all active ingredients, and only gives a kind of administration time-histories of active ingredient again after a period of time, and vice versa.
Therefore, the present invention comprises also and is other forms of pharmaceutical compositions of branch that one of them dosage form comprises SGLT2 inhibitor, DPP IV inhibitor and the 3rd therapeutic agent, and another dosage form only comprises the 3rd therapeutic agent.
The pharmaceutical composition that be out of the ordinary or a plurality of dosage forms, preferably is test kit is applicable in the combination treatment, to satisfy patient's individualized treatment needs neatly.
According to first embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form that comprises SGLT2 inhibitor and at least a pharmaceutically acceptable carrier, and
(b) second container, it contains the dosage form that comprises DPP IV inhibitor and at least a pharmaceutically acceptable carrier, and
(c) the 3rd container, it contains the dosage form that comprises the third antidiabetic drug and at least a pharmaceutically acceptable carrier.
According to second embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form that comprises SGLT2 inhibitor and the third antidiabetic drug and at least a pharmaceutically acceptable carrier, and
(b) second container, it contains the dosage form that comprises DPP IV inhibitor and at least a pharmaceutically acceptable carrier.
According to the 3rd embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form that comprises SGLT2 inhibitor and at least a pharmaceutically acceptable carrier, and
(b) second container, it contains the dosage form that comprises DPP IV inhibitor and the third antidiabetic drug and at least a pharmaceutically acceptable carrier.
According to the 4th embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form that comprises SGLT2 inhibitor and DPPIV inhibitor and at least a pharmaceutically acceptable carrier, and
(b) second container, it contains the dosage form that comprises the third antidiabetic drug and at least a pharmaceutically acceptable carrier.
Another aspect of the invention is a kind of goods, it comprises other forms of pharmaceutical compositions of branch and label or the package insert of being of the present invention, and this label or package insert comprise the explanation of other dosage form of branch to make up or alternately to give.
According to first embodiment, goods comprise the pharmaceutical composition that (a) comprises SGLT2 inhibitor of the present invention; And (b) label or package insert, its comprise medicine can be for example with the medicine that comprises DPP IV inhibitor of the present invention and the medicine that comprises the medicine of the third antidiabetic drug of the present invention or comprise DPPIV inhibitor of the present invention and the third antidiabetic drug with combination alternately give or with its combination or the explanation that alternately gives.
According to second embodiment; Goods comprise pharmaceutical composition and (b) label or the package insert that (a) comprises DPP IV inhibitor of the present invention, its comprise medicine can be for example with the medicine that comprises SGLT2 inhibitor of the present invention and the medicine that comprises the medicine of the third antidiabetic drug of the present invention or comprise SGLT2 inhibitor of the present invention and the third antidiabetic drug with combination or alternately give or treat and its combination or the explanation that alternately gives.
According to the 3rd embodiment; Goods comprise pharmaceutical composition and (b) label or the package insert that (a) comprises DPP IV inhibitor of the present invention and the third antidiabetic drug, its comprise medicine can be for example with the medicine that comprises SGLT2 inhibitor of the present invention with combination or alternately give or treat and its combination or the explanation that alternately gives.
According to the 4th embodiment; Goods comprise pharmaceutical composition and (b) label or the package insert that (a) comprises SGLT2 inhibitor of the present invention and the third antidiabetic drug, its comprise medicine can be for example with the medicine that comprises DPPIV inhibitor of the present invention with combination or alternately give or treat and its combination or the explanation that alternately gives.
The required dosage of pharmaceutical composition of the present invention provides with the fractionated dose that provides once a day or give with appropriate intervals (for example twice of every day, more than three times or three times dosage) easily.
Pharmaceutical composition can through prescription be used to be the liquid or solid form or be suitable for that the form that gives is oral through sucking or being blown into, per rectum, per nasal, part (comprising buccal and Sublingual), percutaneous, transvaginal or parenteral (comprising intramuscular, subcutaneous and intravenous) give.Preferred oral gives.If suitable, then preparation should be discontinuous dosage device, and can be by any method preparation of knowing in the drug world.All methods include following steps: the pharmaceutically acceptable carrier of active ingredient and one or more (like liquid-carrier or fine-powdered solid carrier or both) is combined, and then to make product shaping in due course be required preparation.
Pharmaceutical composition can be following form through prescription: tablet, granule, fine grained agent, powder, capsule, Caplet, soft capsule, pill, oral administration solution, syrup, dry syrup, chewable tablet, coated tablet, effervescent tablet, drop, suspension, instant, oral quick dispersible tablet etc.
Pharmaceutical composition and dosage form preferably comprise one or more pharmaceutically acceptable carriers.Preferred vector must " can be accepted ", and the meaning is meant compatible with other composition of preparation and harmless to its receiver.The instance of pharmaceutically acceptable carrier is known to those skilled in the art.
The pharmaceutical composition that is suitable for orally give should be discontinuous unit form, and capsule for example comprises Perle, cachet or the tablet of the active ingredient that respectively contains scheduled volume; Powder or granule; Solution, suspension or emulsion, for example syrup, elixir or self emulsifying transmission system (SEDDS).Active ingredient also can be bolus (bolus), electuary (electuary) or paste form.The tablet and the capsule that are used for orally give can contain knows excipient, for example binding agent, filler, lubricant, disintegrating agent or wetting agent.Can be according to the method coated tablet of knowing in this technology.Oral liquid can be following form, for example aqueous or oily suspensions, solution, emulsion, syrup or elixir; Maybe can be before use with water or the restorative dry products of other suitable mediator.These liquid preparations can contain knows additive, for example suspending agent, emulsifying agent, non-aqueous mediator (it can comprise edible oil) or antiseptic.
Pharmaceutical composition of the present invention also can be filled a prescription and is used for parenteral (for example through injection, for example quick intravenous injection or continuous infusion), and can be the unit dosage forms in ampoule, pre-filled syringe, small size infusion or the multi-dose container that adds antiseptic.Compositions can adopt the form of the for example suspension in oiliness or aqueous vehicles, solution or emulsion and can contain the for example formula agent of suspending agent, stabilizing agent and/or dispersant.Perhaps, active ingredient can be through aseptic separation sterile solid or the powder form through obtaining from the solution lyophilizing, and it is before use to be fit to mediator (for example aseptic apirogen water) reconstruct.
Carrier is the suppository form that the solid pharmaceutical composition that is suitable for rectally most preferably is unit dose.Suitable carrier comprises cocoa butter and other material usually used in this field, and suppository should pass through mixed active chemical compound and softening or fusion carrier, and being shaped with postcooling and in mould forms.
Compare with one or both pharmaceutical composition and the method in only comprising three kinds of active ingredients, pharmaceutical composition of the present invention and method show treatment and prevent those diseases mentioned above and the advantageous effect of disease.For example can find advantageous effect about effect, dosage specification, dose frequency, pharmacodynamic profiles, pharmacokinetic properties, less untoward reaction, convenience, compliance etc.
The known method for preparing SGLT2 inhibitor of the present invention and prodrug thereof of those skilled in the art.Advantageously, The compounds of this invention uses the synthesis method preparation that comprises described in the patent application document of above quoting.The preferred for preparation method is described among WO2006/120208 and the WO 2007/031548.About preferred compound (I.9), favourable crystal form is described in the International Patent Application WO 2006/117359, and it is incorporated herein by reference in full.
About Li Lalieting, synthesis method known by the technical staff and described in document, especially described in WO2002/068420, WO 2004/018468 or WO 2006/048427, the disclosure of these documents is incorporated herein.The polymorphic crystal modification and the preparation of concrete DPP IV inhibitor are disclosed in respectively among WO 2007/128721 and the WO 2007/128724, and the disclosure of these documents is incorporated herein by reference.
The synthesis method of other DPP IV inhibitor is described in scientific literature and/or the disclosed patent documentation, in the document of especially above quoting.
Active ingredient, especially DPP IV inhibitor and/or the third antidiabetic drug can be the pharmaceutically acceptable salt form.Pharmaceutically acceptable salt includes, but is not limited to the for example salt of mineral acid, this mineral acid example hydrochloric acid, sulphuric acid and phosphoric acid; The salt of organic carboxyl acid, this organic carboxyl acid such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid, and the salt of organic sulfonic acid, this organic sulfonic acid such as Loprazolam and p-methyl benzenesulfonic acid.Can form salt with acid through the chemical compound that in solvent and distintegrant, mixes appropriate amount and ratio.It also can be through carrying out cation or anion exchange acquisition with other salt form.
Active ingredient or its pharmaceutically acceptable salt can be the solvate form thereof of hydrate for example or alcohol adducts (alcohol adduct).
Can be by any combinations thereof and the method in the animal model test scope of the invention as known in the art.Hereinafter, experiment in the body of the pharmacology's correlation properties be suitable for assessing pharmaceutical composition of the present invention and method is described:
Test pharmaceutical composition of the present invention and method in like the hereditary hyperinsulinemia property of db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rat or Zucker DiabeticFatty (ZDF) rat or diabetic animal.In addition, it can be tested in like the animal of bringing out diabetes through the experiment of pretreated HanWistar of streptozotocin (streptozotocin) or Sprague Dawley rat.
Can be after single give to reach the SGLT2 inhibitor and DPP IV inhibitor and the third antidiabetic drug of combination separately, test the present invention makes up the effect to glycemic control in oral glucose tolerance test in animal model mentioned above.In the overnight fasting animal, carry out oral glucose and stimulate (glucose challenge) afterwards, the time-histories of follow-up investigation blood glucose.Reduce or glucose AUC reduces measuredly like peak glucose concentration, with each monotherapy or only use in three kinds of active ingredients the dual combination treatment of two kinds combination to compare, the present invention makes up the remarkable glucose fluctuation that improves.In addition, in animal model mentioned above, repeatedly give after the SGLT2 inhibitor and DPP IV inhibitor and the third antidiabetic drug alone or in combination, can be through the effect of the HbAlc pH-value determination pH in the measurement blood to glycemic control.Compare with each monotherapy or dual combination treatment (promptly use only two kinds combination in three kinds of active ingredients, for example adopt the SGLT2 inhibitor to add the third antidiabetic drug or DPPIV inhibitor and the 3rd therapeutic agent), the present invention makes up remarkable reduction HbAlc.
By mentioned earlier in the animal model than the effect of the combination of low dosage and monotherapy or dual combination treatment to glycemic control, the possible dosage of one or more in test SGLT2 inhibitor, DPPIV inhibitor and the third antidiabetic drug reduces.Compare with placebo treatment, make up the remarkable glycemic control of improving than the present invention of low dosage, then invalid than the monotherapy or the dual combination treatment of low dosage.
In animal model mentioned above, in oral glucose tolerance test, behind the single-dose, can show the dependent/non-dependent that treatment of the present invention improves insulin.In the overnight fasting animal, carry out after the glucose stimulation time-histories of follow-up investigation plasma insulin.Compare with independent DPP IV inhibitor, SGLT2 inhibitor combination DPP IV inhibitor and the third antidiabetic drug will show lower insulin peak concentration or INSULIN A UC under than the hypoglycemia fluctuation.
The increase of these content that can cause through treatment of the present invention after the active GLP-1 content in the blood plasma of measurement animal model mentioned above is confirmed the single or multiple administration down at state on an empty stomach or after the meal.Equally, can measure the reduction of glucagon content in the blood plasma under the same conditions.Compare with independent SGLT2 inhibitor, SGLT2 inhibitor combination DPP IV inhibitor and the third antidiabetic drug will show higher active GLP-1 concentration and lower glucagon concentration.
Can be in animal model mentioned above behind the multiple dosing, through the increase of measurement insulin content or through after the histochemical stain of pancreas partial immunity, measuring the β cell quality of increase or confirm the effect of the combination of SGLT2 inhibitor of the present invention, DPP IV inhibitor and the third antidiabetic drug to β cell regeneration and new life's excellence through the insulin secretion that the glucose that increases in the measurement warp separation islets of langerhans stimulates through morphological analysis.
Pharmacological examples
Following examples show the beneficial effect of the present invention's combination to glycemic control.
Embodiment 1:
According to first embodiment, at male Zucker rat (Crl:ZUC (Orl) Lepr of overnight fasting Fa) or Zucker Diabetic Fatty (ZDF) rat (ZDF/Crl-Lepr Fa/ carry out oral glucose tolerance test in Crl).Get blood through afterbody and obtain blood sample before the administration.With the blood glucose meter measuring blood, and the animal random packet is used for blood sugar test (every group of n=5).Subsequently; The independent mediator (0.5% hydroxyethyl cellulose aqueous solution that contains 0.015%Polysorbat 80) that each winding is given by single oral, or contain SGLT2 inhibitor or DPPIV inhibitor or the third antidiabetic drug or SGLT2 inhibitor and add the mediator that the DPPIV inhibitor adds the combination of the third antidiabetic drug.Perhaps, also can after repeatedly dividing other medicine, test, need the long period could produce tangible antidiabetic effect with confirmation, as the situation of thiazolidinedione.After giving drug compound 30 minutes, animals received oral glucose load (2g/kg).Glucose stimulated 30 minutes, 60 minutes, 90 minutes and 120 minutes afterwards, measured the blood glucose in the afterbody blood.Come quantitative glucose fluctuation through calculating glucose AUC.Data are represented with meansigma methods ± SEM.Use bilateral non-matching student's t method of inspection (Student ' s t test) to come statistical matched group and active group.Carry out statistical by student t method of inspection.
Following specific embodiment shows, compares SGLT2 inhibitor (I.9) and DPPIV inhibitor Li Lalieting and glycemic control is had excellent effect with combination as the metformin of the third antidiabetic drug with dividing other monotherapy and dual combination.With use all relevant experimental programs of laboratory animal all to pass through federal Ethics Committee (federal Ethics Committee) to appraise through discussion and ratify through government department.After the male Zucker rat of overnight fasting mentioned above carried out the single oral administration, carry out oral glucose tolerance test.Control animal is only accepted mediator.Compd A is through the substituted benzene derivative of glucopyranosyl (I.9), and dosage is every kg body weight 0.5mg.Compd B is Li Lalieting, and dosage is every kg body weight 0.5mg.Met is a metformin, and dosage is every kg body weight 50mg.In this combination, each chemical compound is to give with dividing the identical dosage of other monotherapy.The result is shown among Fig. 1.
With of the symbolic representation of matched group P value relatively by the strip top.Be used for three recombinations and the P value representation that divide other dual combination and monotherapy in figure below (#, p＜0.1 of comparison through the substituted benzene derivative of glucopyranosyl, Li Lalieting and metformin; *, p＜0.05; *, p＜0.01; * *, p＜0.001).Think less than 0.05 p value tool statistical significance, and think 0.1 to 0.05 p value demonstration trend.
In following table 3, provide one group of complete p value of the comparison of all groups.
A B Met A+Met B+Met A+B A+B+Met
Contrast n.s. n.s. n.s. # * * **
A n.s. n.s. * * ** ***
B n.s. # # # *
Met # # * **
A+Met n.s. n.s. *
B+Met n.s. *
A+B *
This paper as the chemical compound of monotherapy under low dosage all not to glucose tolerance generation effect.Be surprisingly found out that; Not only when comparing with each monotherapy; But also when comparing with each dual combination; Three recombinations of the substituted benzene derivative markon of glucopyranosyl La Lietingjia metformin make glucose fluctuation significantly reduce by 16% with respect to matched group, and this of total glucose AUC is reduced in and has significance on the statistics.
Embodiment 2:
According to second embodiment, carry out oral glucose tolerance test in the male Sprague Dawley of the overnight fasting rat (Crl:CD (SD)) of about 200g in body weight.Get blood through afterbody and obtain blood sample before the administration.With the blood glucose meter measuring blood, and the animal random packet is used for blood sugar test (every group of n=5).Subsequently, each winding is subjected to the independent mediator (0.5% hydroxyethyl cellulose aqueous solution that contains 0.015%Polysorbat 80) that single oral gives or contains the SGLT2 inhibitor or DPPIV inhibitor or the third antidiabetic drug or SGLT2 inhibitor add the mediator that DPP IV inhibitor adds the combination of the third antidiabetic drug.Perhaps, each winding is subjected to the independent mediator that single oral gives or contains the SGLT2 inhibitor or the DPPIV inhibitor adds the third antidiabetic drug or the third antidiabetic drug or SGLT2 inhibitor and adds the mediator that DPP IV inhibitor adds the combination of the third antidiabetic drug.Perhaps, also can after multiple dosing divides other medicine, test, with explanation need the long period could occur with the thiazolidinedione situation in the same tangible antidiabetic effect.After giving drug compound 30 minutes, animals received oral glucose load (2g/kg).Glucose stimulated 30 minutes, 60 minutes, 90 minutes and 120 minutes afterwards, measured the blood glucose in the afterbody blood.Come quantitative glucose fluctuation through calculating glucose AUC.Data are represented with meansigma methods ± S.E.M.Carry out statistical by student t method of inspection.
Embodiment 3: the treatment pre-diabetes
Can use clinical research to test the effect of pharmaceutical composition of the present invention in treating the pre-diabetes that is reduced to characteristic with pathologic fasting glucose and/or glucose tolerance.In research than short-term (for example 2-4 week); Measure fasting glucose value and/or after the meal or the dextrose equivalent behind the Road test (in oral glucose tolerance test after the set dining or the test of food toleration) through finishing the back treatment period in research, and it is relatively checked with these values of these values and/or placebo group before the research beginning treat success property.In addition, measure fructosamine (fructosamine) value after can before treatment, reaching, and compare with initial value and/or placebo value.The remarkable reduction of empty stomach or non-empty stomach glucose content confirms therapeutic efficiency.In the research of long term (12 week or more than 12 weeks), through measuring HbAlc value, relatively testing with initial value and/or placebo class value and treat success property.Compare with initial value and/or placebo value, the remarkable change of HbAlc value has proved that the present invention's combination is used to treat the effect of pre-diabetes.
Embodiment 4: prevention dominance type ii diabetes
Treatment pathologic fasting glucose and/or glucose tolerance reduce (pre-diabetes) patient and also pursue the target that prevention is transformed into the dominance type ii diabetes.Can in comparative clinical research, investigate therapeutic efficiency, wherein with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines treatment pre-diabetes patient through overlength period (for example 1-5).When during treating, reaching the treatment end; Test through measuring fasting glucose and/or Road test (for example oGTT); To confirm that how many patients show the dominance type ii diabetes, i.e. fasting glucose content＞125mg/dl and/or according to 2 one hour values＞199mg/dl of oGTT.Compare with a kind of treatment of other form, during with the present invention's medicine combined therapy, show the remarkable minimizing of dominance type ii diabetes patient quantity, proved that prevention is transformed into the effect of overt diabetes from pre-diabetes.
Embodiment 5: the treatment type ii diabetes
With medicine composite for curing type ii diabetes patient of the present invention, except the glucose metabolism situation is produced the improvement fast, also long-term prevention of metabolic situation worsens.Can with the medicine composite for curing of the present invention long term (for example 3 months to 1 year or even 1 to 6 year) and with patient patient relatively with the treatment of other antidiabetic medicine in observe this result.If observe fasting glucose and/or HbAlc value does not increase or only slightly increase, then evidence shows with the patient who treats with other antidiabetic medicine and compares, and treats successfully.If compare with patient with the other medicines treatment; The glucose metabolism situation with the patient of medicine composite for curing of the present invention of remarkable less percentage ratio worsen (for example HbAlc value increase to＞6.5% or＞7%) to the degree that indication need be treated with extra oral antidiabetic thing or insulin or insulin analog, then further obtain evidence and show and treat successfully.
Embodiment 6: the treatment insulin resistance
In the clinical research of different time length (for example 2 thoughtful 12 months), use hyperinsulinemia property-euglycemia clamp to study and check treatment success property.Compare with initial value or placebo group or the group that gives different therapies, glucose infusion speed significantly raises when research finishes, and has proved the effect of medicine composite for curing insulin resistance of the present invention.
Embodiment 7: the treatment hyperglycemia
In the clinical research of different time length (for example 1 day to 24 months), through measuring fasting glucose or non-fasting glucose (for example after the meal or behind the oGTT Road test or limit the back of having meal) the treatment success property of check in the hyperglycemia patient.Compare with initial value or placebo group or the group that gives different therapies, during studying or research when finishing these dextrose equivalents significantly reduce, proved the effect of medicine composite for curing hyperglycemia of the present invention.
Embodiment 8: prevention blood capillary or trunk complication
With medicine composite for curing type ii diabetes of the present invention or pre-diabetes patient, prevent or reduced microvascular complication (for example diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer) or trunk complication (for example myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia, vascular restenosis) or reduced the risk that develops these complication.With the combination of pharmaceutical composition of the present invention or active ingredient of the present invention long-term (for example 1-6) treatment type ii diabetes or pre-diabetes patient, and with relatively with the patient of other antidiabetic medicine or placebo treatment.Compare with the patient with other antidiabetic medicine or placebo treatment, the negligible amounts of single-shot property or multiple complication shows and treats successfully.In the situation of trunk incident, diabetic foot and/or diabetic ulcer, through medical history and various test number of computations.In the situation of diabetic retinopathy, illumination through the optical fundus being carried out computer control and assessment or other ophthalmology method confirm to treat success property.In the situation of diabetic neuropathy, except medical history and Clinical Laboratory, also can use the tuning fork of for example calibration to measure nerve conduction velocity.About diabetic nephropathy, can be before research beginning, during the research and research study following parameter when finishing: albumin secretion, creatinine clearance, serum creatinine value, serum creatinine value double the used time, until must the used time of dialysis.
Embodiment 9: the treatment metabolism syndrome
Can be in the clinical research of different time length (for example 12 thoughtful 6 years) through measuring the effect that fasting glucose or non-fasting glucose (for example after the meal or behind the oGTT Road test or limit the back of having meal) or HbAlc value are tested pharmaceutical composition of the present invention.Compare with initial value or placebo group or the group that gives different therapies, during studying or research these dextrose equivalents or significantly reduction of HbAlc value when finishing, proved the effect of the combined therapy metabolism syndrome of active ingredient or active ingredient.The example is for comparing with the initial value in when beginning research or with patient's group of placebo or different therapy for treating, and systolic pressure and/or diastolic pressure reductions, plasma triglyceride reduction, T-CHOL or LDL cholesterol reduce, the HDL cholesterol raises or the body weight reduction.
Embodiment 10a: prevention NODAT and/or PTMS and NODAT/PTMS related complication
Patient with after the medicine composite for curing organ transplantation of the present invention has prevented the development of NODAT and/or PTMS and related complication.Can in comparative clinical research, investigate the effect of treatment, wherein with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines patient or firm patient who has transplanted before ultra-long time (for example 1-5) treatment is transplanted.When during therapy, reaching the therapy end, will evaluate NODAT, PTMS, blood capillary and trunk complication, transplant rejection, infection and dead sickness rate.The quantity that experiences the patient of these complication significantly reduces, and confirms the effect of prevention NODAT, PTMS and related complication development.
The treatment prevention of embodiment 10b:NODAT and/or PTMS, delay or the relevant complication of minimizing
Use medicine composite for curing NODAT of the present invention and/or PTMS patient, prevented, postponed or reduced the development of NODAT/PTMS related complication.Can in comparative clinical research, investigate the effect of treatment, wherein with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines through ultra-long time (for example 1-5) treatment NODAT and/or PTMS patient.When during therapy, reaching the therapy end, will evaluation blood capillary and trunk complication, transplant rejection, infection and dead sickness rate.The quantity that experiences the patient of these complication significantly reduces, and has proved prevention, delay or has reduced NODAT and/or the effect of PTMS related complication development.
Embodiment 11a: treatment gestational diabetes
In the clinical research in short period (for example 2-4 week); Measure fasting glucose value and/or after the meal or the dextrose equivalent behind the Road test (limiting oral glucose tolerance test or food-tolerance test after having meal) through finishing the back treatment period in research, and it is relatively checked with these values of these values and/or placebo group before the research beginning treat success property.In addition, measure the fructose amine number after can before treatment, reaching, and compare with initial value and/or placebo value.The remarkable reduction of empty stomach or non-empty stomach glucose content has proved the effect of pharmaceutical composition of the present invention.
In longer-term research (12 weeks or more than 12 weeks), through measure HbAlc value (with initial value and placebo group relatively) check treats success property.Compare with initial value and/or placebo value, the remarkable change of HbAlc value has proved the effect of medicine composite for curing gestational diabetes of the present invention.
Embodiment 11b: the women of gestational diabetes is suffered from treatment
The gestational diabetes patient is after pregnancy, and the risk of suffering from the dominance type ii diabetes significantly increases.Can provide purpose to be to prevent to be transformed into the treatment of dominance type ii diabetes.For this purpose, the women who has the gestational diabetes medical history with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines through ultra-long time (for example 1-4) treatment.When during treating, reaching the treatment end; Through measuring fasting glucose and/or check, there are how many patients to develop dominance type ii diabetes (2 one hour values behind fasting glucose content＞125mg/dl and/or the oGTT＞199mg/dl) with understanding by Road test (for example oGTT).Compare with dissimilar therapies; When with medicine composite for curing of the present invention; The patient's of development dominance type ii diabetes quantity significantly reduces, and this has proved the effect of this pharmaceutical composition prevention overt diabetes in having the women who suffers from the gestational diabetes medical history.
Embodiment 12: the treatment hyperuricemia
Uric acid content be increased to the patient of normal value above (greater than 8.3mg/dL or 494 μ mol/L) have gout or gouty arthritis medical history and uric acid content high greater than the risk of the patient's following outbreak gout of 6.0mg/dL or 357 μ mol/L or gouty arthritis, and suffer from cardiovascular disease risk and increase.The treatment that can provide purpose to be to reduce serum uric acid content is as the method for the following outbreak of prevention or burst gout or gouty arthritis.In addition, reduce serum uric acid content and can reduce the trouble cardiovascular disease risk.For this purpose, have the patient of metabolic arthritis content or have gout or the patient of gouty arthritis medical history through ultra-long time (for example 6 months to 4 years) treatment with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines.During treating and when treatment finishes, check through the attack times of measuring serum uric acid content and gout or gouty arthritis.Compare with dissimilar therapies; When with medicine composite for curing of the present invention; Uric acid is reduced to 6.0mg/dL following and/or gout or the minimizing of gouty arthritis attack times, has proved that this pharmaceutical composition has the effect of prevention gout or gouty arthritis outbreak or treatment hyperuricemia.
Embodiment 13: the treatment hyponatremia
Hyponatremia and water intoxication (being absorbed again to increase by water to cause or caused by water absorption increase no matter be) patient is in the unusual risk of central nervous system, and maybe be dead.Can provide purpose to be to increase to secrete the amount of the free water in kidney filtrating and not disturb sodium balance, thereby reach the treatment of the total na concn that increases interstitial fluid.For this purpose, with the patient that pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines have the hyponatremia medical history through short-term (for example 3 months to 6 months) treatment, regular assessment serum sodium content.Compare with dissimilar therapies, when with medicine composite for curing of the present invention, the sodium content of being reported increases to normal range during this period, has proved that this pharmaceutical composition has the effect of treatment hyponatremia.
Embodiment 14: treatment/prevention renal calculus
Patient with renal calculus (especially calcium, calcium mixture and urate calculus) medical history has the hyperuricemia medical history usually.These renal calculuss maybe be relevant with little urate crystal formation focus in kidney filtrating, and the further crystallization of other crystalline material in urate after this or the solute can be brought out renal calculus and form.It is irrelevant that these calculus and some kidneys infect the renal calculus (for example staghorn stone) that causes.The treatment that can provide purpose to be to increase the content of neutral solute (for example glucose) and free water in the kidney filtrating, although so that in the kidney filtrating uratic absolute magnitude possibly increase, be difficult to form the urate focus.The calculus that these neutral solutes and free water also will reduce except that urate calculus forms.For this purpose, the patient who has renal calculus (especially calcium, calcium mixture and urate calculus) medical history through ultra-long time (for example 6 months to 4 years) treatment with pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines.Compare with dissimilar therapies; During this period; When with medicine composite for curing of the present invention, the quantity of the renal calculus of being reported (especially calcium, calcium mixture and urate calculus) reduces, and has proved that pharmaceutical composition has the effect of prevention renal calculus (especially calcium, calcium mixture and urate calculus).
FORMULATION EXAMPLE
The embodiment that can be similar to the following preparation that known method obtains in this area is used to illustrate in greater detail the present invention, but not limit the invention in the content of these embodiment.One or more The compounds of this invention represented in term " active ingredient "; Promptly represent the combination of SGLT2 inhibitor of the present invention, DPP IV inhibitor or the 3rd antidiabetic compound or two or three these active ingredients, for example be selected from like combination listed in table 1 or 2.Other suitable preparation of DPP IV inhibitor Li Lalieting can be incorporated herein by reference the disclosure of this application like disclosed preparation among the application WO2007/128724.Other DPP? IV inhibitors other suitable formulation is commercially available preparations are commercially available, or the above "prior art" patent applications cited in the paragraph described in preparation or preparations as those described in the literature, for example, is Journal
Figure BDA0000081995560000551
(Germany) or the "Physician's? Desk? Reference" in the formulations disclosed.
Embodiment 1: every 10ml contains the dry ampoule of 75mg active ingredient
Form:
Active ingredient 75.0mg
Mannitol 50.0mg
Water for injection is supplied 10.0ml
Preparation:
Active ingredient and mannitol are dissolved in the water.After the encapsulation, with the solution lyophilization.In order to make instant solution, product is dissolved in the water for injection.
Embodiment 2: every 2ml contains the dry ampoule of 35mg active ingredient
Form:
Active ingredient 35.0mg
Mannitol 100.0mg
Water for injection is supplied 2.0ml
Preparation:
Active ingredient and mannitol are dissolved in the water.After the encapsulation, with the solution lyophilization.In order to make instant solution, product is dissolved in the water for injection.
Embodiment 3: the tablet that contains the 50mg active ingredient
Form:
Preparation:
With the aqueous solution of (1), (2) and (3) and (4) together and granulate.To in the drying and granulating material, adding (5).Mixture compressed tablets thus, these tablets are that biplanar, bilateral has facet and on a side, the indenture of cutting apart arranged.
Tablet diameters: 9mm.
Embodiment 4: the tablet that contains the 350mg active ingredient
Preparation:
Figure BDA0000081995560000562
With the aqueous solution of (1), (2) and (3) and (4) together and granulate.To in the drying and granulating material, adding (5).Mixture compressed tablets thus, these tablets are that biplanar, bilateral has facet and on a side, has the indenture of cutting apart.
Tablet diameters: 12mm.
Embodiment 5: the tablet that contains the 850mg active ingredient
Preparation:
Figure BDA0000081995560000572
With the aqueous solution of (1), (2) and (3) and (4) together and granulate.To in the drying and granulating material, adding (5).Mixture compressed tablets thus, these tablets are that biplanar, bilateral has facet and on a side, has the indenture of cutting apart.
Tablet diameters: 12mm.
Embodiment 6: the capsule that contains the 50mg active ingredient
Form:
Figure BDA0000081995560000573
Preparation:
Grind (1) with (3).Under violent the mixing, this abrasive material is added in the mixture of (2) and (4).In capsule filling machine, this mixture of powders is packaged in No. 3 hard gelatin capsules.
Embodiment 7: the capsule that contains the 350mg active ingredient
Form:
Figure BDA0000081995560000581
Preparation:
Grind (1) with (3).Under violent the mixing, this abrasive material is added in the mixture of (2) and (4).In capsule filling machine, this mixture of powders is packaged in No. 0 hard gelatin capsule.

Claims (22)

1. pharmaceutical composition, it comprises,
(a) the SGLT2 inhibitor and
(b) the DPPIV inhibitor and
(c) be selected from the third antidiabetic drug of following G3 group: biguanide, thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor, GLP-1 analog or its pharmaceutically acceptable salt.
2. the pharmaceutical composition of claim 1, wherein this SGLT2 inhibitor is selected from following G1 group: the substituted benzene derivative of glucopyranosyl that Da Gelie is clean, Kan Gelie is clean, A Gelie is clean, Rui Gelie is clean, She Gelie reaches formula (I) only, or its prodrug
Figure FDA0000081995550000011
R wherein 1Expression Cl, methyl or cyanic acid, R 2Expression H, methyl, methoxyl group or hydroxyl and R 3Expression ethyl, cyclopropyl, acetenyl, ethyoxyl, (R)-oxolane-3-base oxygen base or (S)-oxolane-3-base oxygen base.
3. claim 1 or 2 pharmaceutical composition; Wherein this DPP IV inhibitor be selected from following G2 group: Li Lalieting, sitagliptin, vildagliptin, A Gelieting, Sa Gelieting, Na Lieting, Ka Gelieting, MAG row spit of fland and Du Gelieting; Or the pharmaceutically acceptable salt of above-mentioned a kind of DPPIV inhibitor, or its prodrug.
4. claim 1,2 or 3 pharmaceutical composition; Wherein this third antidiabetic drug is selected from: metformin, pioglitazone, rosiglitazone, troglitazone, ciglitazone, glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride, glibenclamide, glisoxepide, gliclazide, Nateglinide, repaglinide, Mitiglinide, acarbose, voglibose, miglitol, Exenatide and Li Lalu peptide, or the pharmaceutically acceptable salt of above-mentioned a kind of therapeutic agent.
5. each pharmaceutical composition during aforesaid right requires is characterized in that said composition is suitable for combination or while or uses this SGLT2 inhibitor, this DPP IV inhibitor and this third antidiabetic drug successively.
6. prevention of metabolic obstacle in the patient of needs; Slow down the progress of this dysbolismus; Postpone or treat the method for this dysbolismus; This dysbolismus is selected from: type i diabetes; Type ii diabetes; Glucose tolerance reduces; Impaired fasting glucose; Hyperglycemia; Postprandial hyperglycemia disease; Overweight; Obesity; Metabolism syndrome; Gestational diabetes; Transplant the diabetes (NODAT) and the relative complication of the new outbreak in back; And metabolism syndrome (PTMS) and relative complication after transplanting, it is characterized in that SGLT2 inhibitor like claim 1 or 2; Like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
7. in the patient who needs is arranged, improve glycemic control and/or reduce fasting plasma glucose, the method for plasma glucose and/or glycosylated hemoglobin HbAlc after the meal, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
8. in the patient who needs is arranged, prevent, slow down, postpone or reverses the method that glucose tolerance reduction, impaired fasting glucose, insulin resistance and/or metabolism syndrome make progress into type ii diabetes, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 to make up or alternately to give this patient.
9. prevention is selected from following disease or obstacle in the patient who needs is arranged; Slow down this disease or obstacle progress; Postpone or treat the method for this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease; Nephropathy for example; Retinopathy; Neuropathy; Tissue ischemia; Diabetic foot; Arteriosclerosis; Myocardial infarction; Acute coronary syndrome; Unstable angina pectoris; Stable angina pectoris; Apoplexy; Peripheral occlusive arterial disease; Cardiomyopathy; Heart failure; Arrhythmia and vascular restenosis is characterized in that the SGLT2 inhibitor like claim 1 or 2; Like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
10. in the patient who needs is arranged, reduce the method that body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
Pancreatic beta cell is degenerated and/or the pancreatic beta cell function reduces and/or improves and/or the method for recovery pancreatic beta cell function and/or recovery insulin secretion function 11. in the patient who needs is arranged, prevent, slow down, postpone or treat, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 to make up or alternately to give this patient.
Unusually accumulate the disease that causes or the medicine of disease 12. in the patient who needs is arranged, prevent, slow down, postpone or treat by dystopy fat, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 to make up or alternately to give this patient.
13. in the patient who needs is arranged, keep and/or improve the method for insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
14. the method for treatment and prevention hyperuricemia and hyperuricemia associated conditions, renal calculus and hyponatremia in the patient who needs is arranged, it is characterized in that like claim 1 or 2 the SGLT2 inhibitor, like the DPP IV inhibitor of claim 1 or 3 and optional the third antidiabetic drug like claim 1 or 4 with combination or alternately give this patient.
15. the SGLT2 inhibitor of claim 1 or 2 is used for the purposes of the medicine of claim 6,7,8,9,10,11,12,13 or 14 method in preparation.
16. the DPP IV inhibitor of claim 1 or 3 is used for the purposes of the medicine of claim 6,7,8,9,10,11,12,13 or 14 method in preparation.
17. the third antidiabetic drug of claim 1 or 4 is used for the purposes of the medicine of claim 6,7,8,9,10,11,12,13 or 14 method in preparation.
18. each pharmaceutical composition is used for having the patient of needs to realize the purposes in the medicine of following purpose in preparation in the claim 1 to 5:
-prevention is selected from following dysbolismus, slows down this dysbolismus progress, postpones or treat this dysbolismus: type i diabetes, type ii diabetes, glucose tolerance reduction, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia disease, overweight, obesity, metabolism syndrome, gestational diabetes; Or
-improve glycemic control and/or reduce fasting plasma glucose, plasma glucose and/or glycosylated hemoglobin HbAlc after the meal; Or
-prevent, slow down, postpone or reverse glucose tolerance reduction, insulin resistance and/or metabolism syndrome and make progress into type ii diabetes; Or
-prevention is selected from following disease or obstacle, slows down this disease or obstacle progress, postpones or treat this disease or obstacle: diabetic complication; For example cataract and blood capillary and trunk disease, for example nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis; Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/or body fat; Or
-prevent, slow down, postpone or treat pancreatic beta cell degeneration and/or the reduction of pancreatic beta cell function, and/or improve and/or recover the function and/or the recovery insulin secretion function of pancreatic beta cell; Or
-prevent, slow down, postpone or treat by dystopy fat and accumulate disease or the disease that causes unusually; Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistance;
-prevention transplant the diabetes (NODAT) of the new outbreak in back and/or transplant after metabolism syndrome (PTMS), slow down these diseases progress, postpone or treat these diseases;
-prevention, delay or minimizing NODAT and/or PTMS related complication comprise blood capillary and trunk disease and incident, transplant rejection, infection and death;
-treatment hyperuricemia and hyperuricemia associated conditions;
-treatment or prevention renal calculus;
-treatment hyponatremia.
19. each purposes in each method or the claim 15 to 18 in the claim 6 to 14, wherein this patient suffers from the individuality that one or more are selected from the disease of overweight, obesity, visceral obesity and abdominal fatness for diagnosis.
20. each purposes in each method or the claim 15 to 18 in the claim 6 to 14, wherein this patient individuality a kind of for showing, two or more following diseases:
(a) fasting glucose or serum glucose concentration are greater than 110mg/dL, especially greater than 125mg/dL;
(b) plasma glucose is equal to or greater than 140mg/dL after the meal;
(c) the HbAlc value is equal to or greater than 6.5%, especially is equal to or greater than 7.0%.
21. each purposes in each method or the claim 15 to 18 in the claim 6 to 14, wherein there is individuality a kind of, two kinds, three kinds or multiple following disease in this patient:
(a) obesity, visceral obesity and/or abdominal fatness,
(b) triglyceride blood content >=150mg/dL,
(c) female patient HDL-cholesteremia liquid hold-up＜40mg/dL and male patient＜50mg/dL,
(d) systolic pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting glucose content >=100mg/dL.
22. each purposes in each method or the claim 15 to 18 in the claim 6 to 14; Although although wherein although this patient has carried out diet and exercise therapy or carried out the monotherapy of this SGLT2 inhibitor, this DPPIV inhibitor or this third antidiabetic drug or carried out two kinds of combination treatments that are selected from the medicine of this SGLT2 inhibitor, this DPPIV inhibitor and this third antidiabetic drug, glycemic control is still insufficient.
CN2010800070254A 2009-02-13 2010-02-11 Pharmaceutical composition comprising an SGLT2 inhibitor, a DPP-IV inhibitor and a third antidiabetic agent, and uses thereof Pending CN102307577A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104203250A (en) * 2012-03-20 2014-12-10 勃林格殷格翰国际有限公司 Pharmaceutical composition comprising empagliflozin and antiobesity drug
CN104418847A (en) * 2013-09-10 2015-03-18 天津药物研究院 Process for preparing 4-(6-deoxidized-beta-D-glucopyranose)-2-[5-(4-fluorophenyl) thiophene-2-methyl]-1-methyl benzol
CN104739835A (en) * 2013-12-30 2015-07-01 中美华世通生物医药科技（武汉）有限公司 Novel pharmaceutical composition for treating diabetes
CN106176718A (en) * 2016-08-03 2016-12-07 上海延安药业有限公司 Compound recipe canagliflozin diformin tablet
CN111870694A (en) * 2020-07-20 2020-11-03 重庆大学 Use of SGLT2 inhibitors
CN112512530A (en) * 2018-07-19 2021-03-16 阿斯利康(瑞典)有限公司 Methods of treating HFpEF using dapagliflozin and compositions comprising dapagliflozin
CN113924096A (en) * 2019-03-25 2022-01-11 乔治全球健康研究院 Low dose triple combination formulation
CN114671839A (en) * 2020-12-25 2022-06-28 天地恒一制药股份有限公司 Solid form compound of dapagliflozin and preparation method and application thereof
WO2024055932A1 (en) * 2022-09-13 2024-03-21 亚宝药业集团股份有限公司 Azacyclic compound, pharmaceutical composition thereof, and use thereof for preventing and/or treating disease

Families Citing this family (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
CA2557801C (en) * 2004-03-16 2013-06-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
UA91546C2 (en) * 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх Crystalline form of 1-chloro-4-(я-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
DE102005035891A1 (en) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
US8507450B2 (en) * 2005-09-08 2013-08-13 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments
PE20080697A1 (en) 2006-05-03 2008-08-05 Boehringer Ingelheim Int BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
CA2810839A1 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh A polymorphic form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-piperidin-1-yl)-xanthine
EP2086991A1 (en) * 2006-10-27 2009-08-12 Boehringer Ingelheim International GmbH CRYSTALLINE FORM OF 4-(ß-D-GLUCOPYRANOS-1-YL)-1-METHYL-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, A METHOD FOR ITS PREPARATION AND THE USE THEREOF FOR PREPARING MEDICAMENTS
CL2008002425A1 (en) * 2007-08-16 2009-09-11 Boehringer Ingelheim Int Pharmaceutical composition comprising an inhibitor of sglt2 and 1- (4-methyl-quinazolin-2-yl) methyl-3-methyl-7 - (- 2-butin-1-yl) -8- (3- (r) -amino- Piperidin-1yl) -xanthine, an iv dpp inhibitor and its use for the treatment of obesity and type 1 and 2 diabetes and complications thereof.
CL2008002427A1 (en) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Pharmaceutical composition comprising 1-chloro-4- (bd-glucopyranos-1-yl) -2- [4 - ((s) -tetrahydrofuran-3-yloxy) benzyl] -benzene combined with 1 - [(4-methylquinazolin- 2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (r) -aminopiperidin-1-yl) xanthine; and its use to treat type 2 diabetes mellitus.
US8648085B2 (en) 2007-11-30 2014-02-11 Boehringer Ingelheim International Gmbh 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders
CL2008003653A1 (en) 2008-01-17 2010-03-05 Mitsubishi Tanabe Pharma Corp Use of a glucopyranosyl-derived sglt inhibitor and a selected dppiv inhibitor to treat diabetes; and pharmaceutical composition.
UA105362C2 (en) 2008-04-02 2014-05-12 Бьорингер Ингельхайм Интернациональ Гмбх 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators
PE20091730A1 (en) 2008-04-03 2009-12-10 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
AU2009270936B2 (en) 2008-07-15 2014-12-18 Theracos, Inc. Deuterated benzylbenzene derivatives and methods of use
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
BRPI0916997A2 (en) 2008-08-06 2020-12-15 Boehringer Ingelheim International Gmbh DPP-4 INHIBITOR AND ITS USE
EA201100446A1 (en) 2008-09-08 2011-10-31 Бёрингер Ингельхайм Интернациональ Гмбх PYRAZOLOPYRIMIDINES AND THEIR APPLICATION FOR THE TREATMENT OF CNS DAMAGE
CN102149407A (en) 2008-09-10 2011-08-10 贝林格尔.英格海姆国际有限公司 Combination therapy for the treatment of diabetes and related conditions
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
BRPI0923121A2 (en) 2008-12-23 2015-08-11 Boehringer Ingelheim Int Saline forms of organic compounds
AR074990A1 (en) 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
JP5600328B2 (en) * 2009-02-13 2014-10-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Pharmaceutical compositions comprising glucopyranosyldiphenylmethane derivatives, pharmaceutical dosage forms thereof, methods for their preparation and their use for improving glycemic control in patients
EP2395983B1 (en) * 2009-02-13 2020-04-08 Boehringer Ingelheim International GmbH Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
EP2395988A2 (en) * 2009-02-13 2011-12-21 Boehringer Ingelheim International GmbH Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics
WO2010092123A1 (en) * 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Sglt-2 inhibitor for treating type 1 diabetes mellitus, type 2 diabete mellitus, impaired glucose tolerance or hyperglycemia
MY156377A (en) 2009-03-31 2016-02-15 Boehringer Ingelheim Int 1-heterocycl-1, 5-dihydro-pyrazolo [3 , 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators
US20110009347A1 (en) * 2009-07-08 2011-01-13 Yin Liang Combination therapy for the treatment of diabetes
KR101813025B1 (en) 2009-09-30 2017-12-28 베링거 인겔하임 인터내셔날 게엠베하 Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
MX2012002942A (en) * 2009-09-30 2012-04-11 Boehringer Ingelheim Int Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)be nzyl)benzene.
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US8163704B2 (en) 2009-10-20 2012-04-24 Novartis Ag Glycoside derivatives and uses thereof
LT2498758T (en) 2009-11-13 2018-11-26 Astrazeneca Ab Bilayer tablet formulations
CN107115530A (en) 2009-11-27 2017-09-01 勃林格殷格翰国际有限公司 Gene diabetes mellitus type utilizes the treatment of DPP IV inhibitor such as BI 1356
US20140088027A1 (en) * 2010-03-30 2014-03-27 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
BR112012028091A2 (en) * 2010-05-05 2016-08-02 Boehringer Ingelheim Int pharmaceutical compositions comprising pioglitazone and linagliptin
KR101927068B1 (en) 2010-05-05 2018-12-10 베링거 인겔하임 인터내셔날 게엠베하 Sequential Combination Therapy by the Weight Reducing Treatment Followed by the DPP-4 Inhibitor
KR101931209B1 (en) 2010-05-11 2018-12-20 얀센 파마슈티카 엔.브이. Pharmaceutical formulations comprising 1-(beta-d-glucopyranosyl)-2-thienyl-methylbenzene derivatives as inhibitors of sglt
WO2011142478A1 (en) * 2010-05-11 2011-11-17 Mitsubishi Tanabe Pharma Corporation Canagliflozin containing tablets
CN102971005A (en) 2010-06-24 2013-03-13 贝林格尔.英格海姆国际有限公司 Diabetes therapy
BR112013003097B1 (en) 2010-08-12 2021-03-16 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones and pharmaceutical composition
WO2012025857A1 (en) * 2010-08-23 2012-03-01 Hetero Research Foundation Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
TWI631963B (en) * 2011-01-05 2018-08-11 雷西肯製藥股份有限公司 Compositions comprising and methods of using inhibitors of sodium-glucose cotransporters 1 and 2
US20130035281A1 (en) 2011-02-09 2013-02-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US8809345B2 (en) 2011-02-15 2014-08-19 Boehringer Ingelheim International Gmbh 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders
AR085689A1 (en) 2011-03-07 2013-10-23 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITIONS OF METFORMIN, LINAGLIPTINE AND AN SGLT-2 INHIBITOR
AU2012241897C1 (en) 2011-04-13 2017-05-11 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of SGLT2
TWI542596B (en) 2011-05-09 2016-07-21 健生藥品公司 L-proline and citric acid co-crystals of (2s,3r,4r,5s,6r)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol
UA113626C2 (en) 2011-06-02 2017-02-27 A COMPOSITION FOR THE TREATMENT OF DIABETES CONTAINING THE DURABLE INSULIN CON conjugate AND THE DUAL ACTION INSULINOTROPIC PIPIDE
US20130035298A1 (en) 2011-07-08 2013-02-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
EP3517539B1 (en) 2011-07-15 2022-12-14 Boehringer Ingelheim International GmbH Substituted dimeric quinazoline derivative, its preparation and its use in pharmaceutical compositions for the treatment of type i and ii diabetes
US20130172244A1 (en) * 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US20130303462A1 (en) 2012-05-14 2013-11-14 Boehringer Ingelheim International Gmbh Use of a dpp-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
EP2727587A1 (en) * 2012-10-30 2014-05-07 Pharnext Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level
DK2981269T3 (en) * 2013-04-04 2023-10-23 Boehringer Ingelheim Vetmedica Gmbh TREATMENT OF METABOLISM DISORDERS IN HORSES
CA2812016A1 (en) 2013-04-05 2014-10-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HUE041709T2 (en) 2013-04-05 2019-05-28 Boehringer Ingelheim Int Therapeutic uses of empagliflozin
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
ES2906115T3 (en) 2013-04-18 2022-04-13 Boehringer Ingelheim Int Pharmaceutical composition, treatment methods and uses thereof
US20140343014A1 (en) * 2013-05-17 2014-11-20 Boehringer Ingelheim International Gmbh Combination of a certain dpp-4 inhibitor and voglibose
KR20240017116A (en) * 2013-12-17 2024-02-06 베링거잉겔하임베트메디카게엠베하 Treatment of metabolic disorders in feline animals
WO2015101916A1 (en) 2013-12-30 2015-07-09 Mylan Laboratories Ltd. Process for the preparation of empagliflozin
ES2951127T3 (en) 2014-01-23 2023-10-18 Boehringer Ingelheim Vetmedica Gmbh SGLT2 inhibitors for the treatment of metabolic disorders in canine animals
JP6615109B2 (en) 2014-02-28 2019-12-04 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Medical use of DPP-4 inhibitors
US10688116B2 (en) 2014-04-01 2020-06-23 Boehringer Ingelheim Vetmedica Gmbh Treatment of metabolic disorders in equine animals
WO2015173584A1 (en) * 2014-05-16 2015-11-19 Astrazeneca Ab Method for suppressing glucagon secretion of an sglt2 inhibitor
EP2992876A1 (en) * 2014-09-05 2016-03-09 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical combinations of sitagliptin
US10555958B2 (en) 2014-09-25 2020-02-11 Boehringer Ingelheim Vetmedica Gmbh Combination treatment of SGLT2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals
EP3217987A4 (en) * 2014-11-10 2018-06-20 Merck Sharp & Dohme Corp. Sglt-2 inhibitors for treating metabolic disorders in patients with renal impairment or chronic kidney disease
AU2016310535B2 (en) 2015-08-27 2021-08-19 Boehringer Ingelheim Vetmedica Gmbh Liquid pharmaceutical compositions comprising SGLT-2 inhibitors
US20170071970A1 (en) 2015-09-15 2017-03-16 Janssen Pharmaceutica Nv Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders
WO2017093419A1 (en) * 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CA3022202A1 (en) 2016-06-10 2017-12-14 Boehringer Ingelheim International Gmbh Combinations of linagliptin and metformin
CN107569678B (en) * 2017-08-31 2020-10-30 华中科技大学同济医学院附属同济医院 Application of liraglutide in preparation of medicine for treating acute and chronic transplant rejection
AU2018351352A1 (en) * 2017-10-19 2020-05-28 Mona E. Buice Topical composition for improved healing of open wounds
WO2019201752A1 (en) * 2018-04-17 2019-10-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
KR102204439B1 (en) * 2018-05-14 2021-01-18 에이치케이이노엔 주식회사 Pharmaceutical Composition comprising SGLT-2 inhibitor and DPP-IV inhibitor
WO2020089760A1 (en) * 2018-11-01 2020-05-07 Glenmark Pharmaceuticals Limited Fixed dose pharmaceutical composition comprising combination of remogliflozin or salt or ester thereof and vildagliptin or salt thereof
BR112021018973A2 (en) * 2019-03-25 2022-02-01 The George Inst For Global Health Low dose triple combination formulation
JP7227427B2 (en) * 2019-07-26 2023-02-21 メッドシャイン ディスカバリー インコーポレイテッド SGLT2/DPP4 inhibitors and uses thereof
WO2021176096A1 (en) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Pharmaceutical composition comprising sglt2 inhibitor
CN115867538A (en) 2020-06-05 2023-03-28 新梅斯托克公司 Preparation of highly pure amorphous dapagliflozin
TR202019590A2 (en) 2020-12-03 2022-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A PROCESS FOR FORMULATIONS OF DAPAGLYFLOZIN AND METFORMIN HYDROCHLORIDE

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930141A (en) * 2004-03-16 2007-03-14 贝林格尔·英格海姆国际有限公司 Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
WO2007093610A1 (en) * 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
WO2008055870A1 (en) * 2006-11-06 2008-05-15 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same

Family Cites Families (268)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3174901A (en) 1963-01-31 1965-03-23 Jan Marcel Didier Aron Samuel Process for the oral treatment of diabetes
NL167151C (en) 1971-04-09 1981-11-16 Acf Chemiefarma Nv PROCESS FOR THE PREPARATION OF MEDICINAL PRODUCTS WITH ANTI-PARASITARY ACTION ON THE BASIS OF HALOGEN CONTAINING THE 2,2'-METHYLENE DIFENOL DERIVATIVES, AND METHOD FOR PREPARING THESE MEDICINAL COMPOUNDS.
JPS5230750A (en) 1975-09-05 1977-03-08 Kobe Steel Ltd High temperature extrusion method for mangannaluminumm carbon magnetic alloy
DE2758025A1 (en) 1977-12-24 1979-07-12 Bayer Ag Tri:hydroxy-piperidine derivs. - useful as glucosidase inhibitors for treating diabetes etc. and as animal feed additives
NO154918C (en) 1977-08-27 1987-01-14 Bayer Ag ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF 3,4,5-TRIHYDROXYPIPERIDINE.
DE2951135A1 (en) 1979-12-19 1981-06-25 Hoechst Ag, 6230 Frankfurt SULFONYL UREAS, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE
JPS5639056A (en) 1980-07-16 1981-04-14 Kanebo Ltd Preparation of n,n,n',n'-tetraacylated nucleus halogenated aromatic diamine
JPS58164502A (en) 1982-03-26 1983-09-29 Chugai Pharmaceut Co Ltd Herbicidal composition
US4602023A (en) 1985-06-03 1986-07-22 Warner-Lambert Company Diphenic acid monoamides
US4786755A (en) 1985-06-03 1988-11-22 Warner-Lambert Company Diphenic acid monoamides
US4802924A (en) 1986-06-19 1989-02-07 Colorcon, Inc. Coatings based on polydextrose for aqueous film coating of pharmaceutical food and confectionary products
US4786023A (en) 1987-08-19 1988-11-22 Harris Leverett D Drafting implement holder
GB9523752D0 (en) 1995-11-21 1996-01-24 Pfizer Ltd Pharmaceutical formulations
DE122010000020I1 (en) 1996-04-25 2010-07-08 Prosidion Ltd Method for lowering the blood glucose level in mammals
US5807580A (en) 1996-10-30 1998-09-15 Mcneil-Ppc, Inc. Film coated tablet compositions having enhanced disintegration characteristics
EP0996508B1 (en) 1997-01-06 2004-08-11 BPSI Holdings, Inc. Film coatings and film coating compositions based on dextrin
AU6024998A (en) 1997-01-15 1998-08-07 Glycomed Incorporated Aryl c-glycoside compounds and sulfated esters thereof
JPH11124392A (en) 1997-10-21 1999-05-11 Sankyo Co Ltd C-glycosylated aryltin compound
CA2819705C (en) 1998-02-02 2014-07-08 Trustees Of Tufts College Method of regulating glucose metabolism, and reagents related thereto
CO5150173A1 (en) 1998-12-10 2002-04-29 Novartis Ag COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION
US6613806B1 (en) 1999-01-29 2003-09-02 Basf Corporation Enhancement of the efficacy of benzoylbenzenes
US6448323B1 (en) 1999-07-09 2002-09-10 Bpsi Holdings, Inc. Film coatings and film coating compositions based on polyvinyl alcohol
CZ303372B6 (en) 1999-08-31 2012-08-22 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivative and pharmaceutical composition containing thereof and benzylpyrazole intermediate
PH12000002657B1 (en) 1999-10-12 2006-02-21 Bristol Myers Squibb Co C-aryl glucoside SGLT2 inhibitors
US6515117B2 (en) * 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
ATE346613T1 (en) 2000-01-21 2006-12-15 Novartis Pharma Gmbh COMPOSITIONS CONSISTING OF DIPEPTIDYLPEPTIDASE-IV INHIBITORS AND ANTIDIABETICS
JP4456768B2 (en) 2000-02-02 2010-04-28 壽製薬株式会社 Drug containing C-glycoside
US6627611B2 (en) 2000-02-02 2003-09-30 Kotobuki Pharmaceutical Co Ltd C-glycosides and preparation of thereof as antidiabetic agents
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6683056B2 (en) 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
US6627634B2 (en) 2000-04-08 2003-09-30 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
AU2001268958B2 (en) 2000-07-04 2006-03-09 Novo Nordisk A/S Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv
IL155071A0 (en) 2000-09-29 2003-10-31 Kissei Pharmaceutical Glucopyranosyloxybenzylbenzene derivatives and medical compositions containing the same
EP1344780A4 (en) 2000-11-30 2004-01-28 Kissei Pharmaceutical Glucopyranosyloxybenzyl benzene derivatives, medicinal compositions containing the same and intermediates in the production thereof
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
EP1354882A1 (en) 2000-12-27 2003-10-22 Kyowa Hakko Kogyo Co., Ltd. Dipeptidyl peptidase iv inhibitor
HU228915B1 (en) 2000-12-28 2013-06-28 Kissei Pharmaceutical Glucopyranosyloxypyrazole derivatives and use thereof
TWI255817B (en) 2001-02-14 2006-06-01 Kissei Pharmaceutical Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof
EA007485B1 (en) 2001-02-24 2006-10-27 Берингер Ингельхайм Фарма Гмбх Унд Ко. Кг Xanthine derivative, method for their production, pharmaceutical composition based thereon and method for their preparation
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
JP3698067B2 (en) 2001-03-30 2005-09-21 Ｊｓｒ株式会社 Monomer having electron-withdrawing group and electron-donating group, copolymer using the same, and proton conducting membrane
AU2002254567B2 (en) 2001-04-11 2007-10-11 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
ATE374181T1 (en) 2001-06-27 2007-10-15 Smithkline Beecham Corp FLUORPYRROLIDINES AS DIPEPTIDYLPEPTIDASE INHIBITORS
US6869947B2 (en) 2001-07-03 2005-03-22 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
JP2005502624A (en) 2001-07-03 2005-01-27 ノボ　ノルディスク　アクティーゼルスカブ Purine derivatives inhibiting DPP-IV for the treatment of diabetes
UA74912C2 (en) 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
WO2003020737A1 (en) 2001-09-05 2003-03-13 Bristol-Myers Squibb Company O-pyrazole glucoside sglt2 inhibitors and method of use
AU2002331311A1 (en) 2001-09-19 2003-04-01 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme dpp-iv
WO2003031458A1 (en) 2001-10-12 2003-04-17 Dana-Farber Cancer Institute Methods for synthesis of diarylmethanes
EP1438053B1 (en) 2001-10-17 2008-09-10 Boehringer Ingelheim Pharma GmbH & Co.KG Pyrimidine derivatives, pharmaceutical agent containing said compounds, use and method for making same
US6723340B2 (en) 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
ATE409466T1 (en) 2002-01-11 2008-10-15 Novo Nordisk As METHOD AND COMPOSITION FOR TREATING DIABETES, HYPERTENSION, CHRONIC HEART FAILURE AND CONDITIONS ASSOCIATED WITH FLUID RETENTION
ES2627842T3 (en) 2002-02-21 2017-07-31 Valeant Pharmaceuticals Luxembourg S.À.R.L. Controlled release dosage forms
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
MXPA04009229A (en) 2002-03-22 2004-11-26 Kissei Pharmaceutical Crystals of glucopyranosyloxybenzyl benzene derivative.
JP4424203B2 (en) 2002-04-26 2010-03-03 味の素株式会社 Diabetes prevention and treatment
DE10231370B4 (en) 2002-07-11 2006-04-06 Sanofi-Aventis Deutschland Gmbh Thiophene glycoside derivatives, medicaments containing these compounds and methods of making these medicaments
TWI254635B (en) 2002-08-05 2006-05-11 Yamanouchi Pharma Co Ltd Azulene derivative and salt thereof
MXPA05001549A (en) 2002-08-08 2005-05-05 Kissei Pharmaceutical Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof.
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
JP4233524B2 (en) 2002-08-21 2009-03-04 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 8- [3-Amino-piperidin-1-yl] -xanthine, its preparation and its use as a pharmaceutical composition
DE10238470A1 (en) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
DE10238477A1 (en) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg New purine derivatives, their production and their use as medicines
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10251927A1 (en) 2002-11-08 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New 1,7,8-trisubstituted xanthine derivatives, are dipeptidylpeptidase-IV inhibitors useful e.g. for treating diabetes mellitus type I or II, arthritis or obesity
EP1562607A1 (en) * 2002-11-15 2005-08-17 Ranbaxy Laboratories, Ltd. Pharmaceutical dosage forms of biguanide-sulfonylurea combinations
JP3567162B1 (en) 2002-11-20 2004-09-22 日本たばこ産業株式会社 4-oxoquinoline compounds and their use as HIV integrase inhibitors
SK2662004A3 (en) 2002-11-20 2005-06-02 Japan Tobacco, Inc. 4-Oxoquinoline compound and its utilisation as integrase inhibitor
DE10254304A1 (en) 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
US7109192B2 (en) 2002-12-03 2006-09-19 Boehringer Ingelheim Pharma Gmbh & Co Kg Substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
UY28103A1 (en) 2002-12-03 2004-06-30 Boehringer Ingelheim Pharma NEW IMIDAZO-PIRIDINONAS REPLACED, ITS PREPARATION AND ITS EMPLOYMENT AS MEDICATIONS
JP4651934B2 (en) 2002-12-04 2011-03-16 キッセイ薬品工業株式会社 Benzylphenol derivative, pharmaceutical composition containing it, and pharmaceutical use thereof
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
DE10258007B4 (en) 2002-12-12 2006-02-09 Sanofi-Aventis Deutschland Gmbh Aromatic fluoroglycoside derivatives, medicaments containing these compounds and methods for the preparation of these medicaments
DE10258008B4 (en) 2002-12-12 2006-02-02 Sanofi-Aventis Deutschland Gmbh Heterocyclic fluoroglycoside derivatives, medicaments containing these compounds and methods of making these medicaments
CA2512389A1 (en) 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Methods of producing c-aryl glucoside sglt2 inhibitors
ES2295816T3 (en) 2003-01-14 2008-04-16 Arena Pharmaceuticals, Inc. ARILO AND HETEROARILO 1,2,3-TRISUSTITUTED DERIVATIVES AS METABOLISM MODULATORS, AND PROFILAXIS AND TREATMENT OF DISORDERS RELATED TO THE SAME, SUCH AS DIABETES AND HYPERGLUCEMIA.
WO2004076470A2 (en) 2003-02-27 2004-09-10 Bristol-Myers Squibb Company A non-cryogenic process for forming glycosides
US7442387B2 (en) 2003-03-06 2008-10-28 Astellas Pharma Inc. Pharmaceutical composition for controlled release of active substances and manufacturing method thereof
EP1980560B1 (en) 2003-03-14 2011-05-25 Astellas Pharma Inc. C-glycoside derivatives for the treatment of diabetes
US7674486B2 (en) 2003-05-14 2010-03-09 Indus Biotech Pvt. Ltd. Synergistic composition for the treatment of diabetes mellitus
AU2004252075A1 (en) 2003-06-03 2005-01-06 The Regents Of The University Of California Compositions and methods for treatment of disease with acetylated disaccharides
JP2004359630A (en) 2003-06-06 2004-12-24 Yamanouchi Pharmaceut Co Ltd Difluorodiphenylmethane derivative and its salt
DE10327439A1 (en) 2003-06-18 2005-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel imidazopyridazinone and imidazopyridone derivatives, their production and their use as pharmaceuticals
KR100730867B1 (en) 2003-06-20 2007-06-20 에프. 호프만-라 로슈 아게 Pyrido[2,1-a]isoquinoline derivatives as dpp-iv inhibitors
JO2625B1 (en) 2003-06-24 2011-11-01 ميرك شارب اند دوم كوربوريشن Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
WO2005009956A1 (en) 2003-07-21 2005-02-03 Smithkline Beecham Corporation (2s,4s)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-l-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt and anhydrous crystalline forms thereof
US20050027236A1 (en) 2003-07-30 2005-02-03 Medtronic Ave, Inc. Aspiration catheter having a variable over-the-wire length and methods of use
CA2549015A1 (en) 2003-08-01 2005-02-10 Janssen Pharmaceutica N.V. Substituted fused heterocyclic c-glycosides
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
BRPI0413232B8 (en) 2003-08-01 2021-05-25 Mitsubishi Tanabe Pharma Corp compound having inhibitory activity against sodium-dependent carrier, pharmaceutical composition comprising the compound, use of the compound in the preparation of a medicine, and process for preparing the compound
JP4131216B2 (en) 2003-08-20 2008-08-13 Ｊｓｒ株式会社 Polyarylene, production method thereof, solid polymer electrolyte and proton conducting membrane
US7375090B2 (en) 2003-08-26 2008-05-20 Boehringer Ingelheim International Gmbh Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof
DE502004008951D1 (en) 2003-08-26 2009-03-19 Boehringer Ingelheim Pharma GLUCOPYRANOSYLOXY-PYRAZOLE, MEDICAMENT CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF
US20050085680A1 (en) 2003-10-21 2005-04-21 Joseph Auerbach Method for industrial decontamination
PT1689757E (en) 2003-11-12 2014-12-09 Sino Med Internat Alliance Inc Heterocyclic boronic acid compounds
KR20150028829A (en) 2003-11-17 2015-03-16 노파르티스 아게 Use of dipeptidyl peptidase iv inhibitors
DE10355304A1 (en) 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 8- (piperazin-1-yl) and 8 - ([1,4] diazepan-1-yl) xanthines, their preparation and their use as pharmaceuticals
DE10359098A1 (en) 2003-12-17 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 2- (piperazin-1-yl) and 2 - ([1,4] diazepan-1-yl) imidazo [4,5-d] pyridazin-4-ones, their preparation and their use as pharmaceuticals
US7371732B2 (en) 2003-12-22 2008-05-13 Boehringer Ingelheim International Gmbh Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture
DE10361133A1 (en) 2003-12-22 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Glucopyranosyloxy-substituted aromatics, medicaments containing these compounds, their use and processes for their preparation
DE10360835A1 (en) 2003-12-23 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg New bicyclic imidazole derivatives are dipeptidylpeptidase-IV inhibitors useful to treat e.g. arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis
ES2940341T3 (en) 2004-01-20 2023-05-05 Novartis Ag Formulation and direct compression process
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
AU2005219508B2 (en) 2004-02-18 2012-02-16 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthine, the production thereof and the use in the form of a DPP inhibitor
DE102004009039A1 (en) 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- [3-Amino-piperidin-1-yl] xanthines, their preparation and use as pharmaceuticals
CN1934103B (en) 2004-03-04 2011-06-01 橘生药品工业株式会社 Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
US7732596B2 (en) 2004-03-04 2010-06-08 Kissei Pharmaceutical Co., Ltd. Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
CN102079743B (en) 2004-03-15 2020-08-25 武田药品工业株式会社 Dipeptidyl peptidase inhibitors
CA2557801C (en) 2004-03-16 2013-06-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
JP2007531780A (en) 2004-04-10 2007-11-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel 2-amino-imidazo [4,5-D] pyridazin-4-one and 2-amino-imidazo [4,5-C] pyridazin-4-one, their preparation and use as pharmaceuticals
US7741082B2 (en) 2004-04-14 2010-06-22 Bristol-Myers Squibb Company Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
PT1753748E (en) 2004-05-12 2009-08-28 Pfizer Prod Inc Proline derivatives and their use as dipeptidyl peptidase iv inhibitors
US7214702B2 (en) 2004-05-25 2007-05-08 Bristol-Myers Squibb Company Process for producing a dipeptidyl peptidase IV inhibitor
TWI415635B (en) 2004-05-28 2013-11-21 必治妥施貴寶公司 Coated tablet formulation and method
WO2005117861A1 (en) * 2004-06-04 2005-12-15 Novartis Ag Use of organic compounds
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
CN1984898A (en) 2004-07-08 2007-06-20 安斯泰来制药有限公司 Process for production of azulene derivatives and intermediates for the synthesis of the same
AU2005261778A1 (en) 2004-07-14 2006-01-19 Novartis Ag Combination of DPP-IV inhibitors and compounds modulating 5-HT3 and/or 5-HT4 receptors
DE102004034690A1 (en) 2004-07-17 2006-02-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Methylidene-D-xylopyranosyl and oxo-D-xylopyranosyl-substituted phenyls, medicaments containing these compounds, their use and processes for their preparation
TW200606129A (en) 2004-07-26 2006-02-16 Chugai Pharmaceutical Co Ltd Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same
JP2008508213A (en) 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング D-glucopyranosyl-phenyl-substituted cyclics, pharmaceuticals containing such compounds, their use and methods for their production
US7689086B2 (en) 2004-07-30 2010-03-30 University Of Connecticut Resonant leaky-mode optical devices and associated methods
WO2006018150A1 (en) 2004-08-11 2006-02-23 Boehringer Ingelheim International Gmbh D-xylopyranosyl-phenyl-substituited cyclene, medicaments containing said compounds, use thereof and method for the production thereof
DE102004043944A1 (en) 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel 8- (3-amino-piperidin-1-yl) -7- (but-2-ynyl) -xanthines, their preparation and their use as pharmaceuticals
DE102004044221A1 (en) 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg New 3-methyl-7-butynyl xanthines, their preparation and their use as pharmaceuticals
AR051446A1 (en) 2004-09-23 2007-01-17 Bristol Myers Squibb Co C-ARYL GLUCOSIDS AS SELECTIVE INHIBITORS OF GLUCOSE CONVEYORS (SGLT2)
DE102004048388A1 (en) 2004-10-01 2006-04-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg D-pyranosyl-substituted phenyls, pharmaceutical compositions containing them, their use and processes for their preparation
JP4959569B2 (en) 2004-10-12 2012-06-27 グレンマーク・ファーマシューティカルズ・エスエー Novel dipeptidyl peptidase IV inhibitors, pharmaceutical compositions containing them, and processes for preparing them
BRPI0518409A2 (en) 2004-10-25 2008-11-18 Novartis Ag combination of dpp-iv inhibitor, ppar antidiabetic and metformin
DE102004054054A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines
WO2006064033A2 (en) 2004-12-16 2006-06-22 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
DE102004063099B4 (en) 2004-12-22 2009-02-12 Sanofi-Aventis Deutschland Gmbh Process for the preparation of thiophene glycoside derivatives
BRPI0518651A2 (en) 2004-12-24 2008-12-02 Dainippon Sumitomo Pharma compound, a prodrug thereof, or a pharmaceutically acceptable compound or prodrug salt, pharmaceutical composition, dipeptidyl peptidase iv inhibitor, use of a compound, a prodrug thereof or a compound or prodrug salt pharmaceutically acceptable method of treating diabetes
DOP2006000008A (en) 2005-01-10 2006-08-31 Arena Pharm Inc COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED AFFECTIONS AND FOR THE TREATMENT OF AFFECTIONS THAT IMPROVE THROUGH AN INCREASE IN THE BLOOD CONCENTRATION OF GLP-1
GT200600008A (en) 2005-01-18 2006-08-09 FORMULATION OF DIRECT COMPRESSION AND PROCESS
TW200637869A (en) 2005-01-28 2006-11-01 Chugai Pharmaceutical Co Ltd The spiroketal derivatives and the use as therapeutical agent for diabetes of the same
ES2334940T3 (en) 2005-02-23 2010-03-17 Boehringer Ingelheim International Gmbh DERIVATIVES OF ((HETERO) ARILETINILBENCIL) BENZENE REPLACED WITH GLUCOPYRANOSIL AND USE OF THE SAME AS INHIBITORS OF THE SODIUM-DEPENDENT GLUCOSE COTRANSPORTER 2 (SGLT2).
ATE453656T1 (en) 2005-04-15 2010-01-15 Boehringer Ingelheim Int GLUCOPYRANOSYL-SUBSTITUTED (HETEROARYLOXY-BENZYL)-BENZENE DERIVATIVES AS SGLT INHIBITORS
US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
UA91546C2 (en) 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх Crystalline form of 1-chloro-4-(я-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
MY152185A (en) 2005-06-10 2014-08-29 Novartis Ag Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
GT200600218A (en) 2005-06-10 2007-03-28 FORMULATION AND PROCESS OF DIRECT COMPRESSION
WO2007000445A1 (en) 2005-06-29 2007-01-04 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
ATE468347T1 (en) 2005-07-27 2010-06-15 Boehringer Ingelheim Int GLUCOPYRANOSYL-SUBSTITUTED ((HETERO)CYCLOALYKLETHYNYL-BENZYL)-BENZENE DERIVATIVES AND THEIR USE AS SODIUM-DEPENDENT GLUCOSE CO-TRANSPORTER (SGLT) INHIBITORS
UY29694A1 (en) 2005-07-28 2007-02-28 Boehringer Ingelheim Int METHODS TO PREVENT AND TREAT METABOLIC AND NEW DISORDERS DERIVED FROM PIRAZOL-O-GLUCOSIDO
DE102005035891A1 (en) 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- (3-amino-piperidin-1-yl) -xanthines, their preparation and their use as pharmaceuticals
MX2008001609A (en) 2005-08-04 2008-02-19 Novartis Ag Salts of vildagliptin.
JP2009504599A (en) 2005-08-11 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー Pharmaceutical composition containing a DPP-IV inhibitor
ATE484499T1 (en) 2005-08-30 2010-10-15 Boehringer Ingelheim Int GLUCOPYRANOSYL-SUBSTITUTED BENZYL DERIVATIVES, MEDICATIONS CONTAINING SUCH COMPOUNDS, THEIR USE AND PRODUCTION METHOD THEREOF
US8507450B2 (en) 2005-09-08 2013-08-13 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments
DK1942898T4 (en) 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for the treatment of diabetes
MY159522A (en) 2005-09-14 2017-01-13 Takeda Pharmaceuticals Co Administration of dipeptidyl peptidase inhibitors
AR056195A1 (en) 2005-09-15 2007-09-26 Boehringer Ingelheim Int PROCEDURES TO PREPARE DERIVATIVES OF (ETINIL-BENCIL) -BENZENE REPLACED GLUCOPYRANOSIL AND INTERMEDIATE COMPOUNDS OF THE SAME
TW200745079A (en) 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
KR101368988B1 (en) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 Dipeptidyl peptidase inhibitors
WO2007035665A1 (en) 2005-09-20 2007-03-29 Novartis Ag Use of a dpp-iv inhibitor to reduce hypoglycemic events
JOP20180109A1 (en) * 2005-09-29 2019-01-30 Novartis Ag New Formulation
NZ567627A (en) 2005-09-30 2011-08-26 Boehringer Ingelheim Vetmed Granulation process for making a divisible tablet containing meloxicam
CA2625646A1 (en) 2005-10-25 2007-05-03 Merck & Co., Inc. Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension
EP1785745A1 (en) 2005-11-10 2007-05-16 Omron Electronics Manufacturing of Germany GmbH Method and operating unit for configuring and monitoring a system with functional safety.
US8414921B2 (en) 2005-12-16 2013-04-09 Merck Sharp & Dohme Corp. Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin
AU2006327069A1 (en) 2005-12-23 2007-06-28 Novartis Ag Condensed heterocyclic compounds useful as DPP-IV inhibitors
JP2009522374A (en) * 2006-01-06 2009-06-11 ノバルティス アクチエンゲゼルシャフト Use of vildagliptin for the treatment of diabetes
US8784886B2 (en) 2006-03-09 2014-07-22 GlaxoSmithKline, LLC Coating capsules with active pharmaceutical ingredients
JP2009531456A (en) 2006-03-28 2009-09-03 武田薬品工業株式会社 Preparation of (R) -3-aminopiperidine dihydrochloride
US20070264370A1 (en) 2006-03-31 2007-11-15 Jeffers Michael G Composition and methods for the treatment of joint pain using Angelica gigas Nakai extract and powder as combined with Glucosamine Sulfate, or Chondroitin Sulfate and HCL, or MSM, or aspirin, or Celedrin, and as combinations thereof in powder, pill, capsule, spray, liquid, and gelcap form
PE20071221A1 (en) 2006-04-11 2007-12-14 Arena Pharm Inc GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS
PE20080697A1 (en) 2006-05-03 2008-08-05 Boehringer Ingelheim Int BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE
CA2810839A1 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh A polymorphic form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-piperidin-1-yl)-xanthine
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
KR20070111099A (en) 2006-05-16 2007-11-21 영진약품공업주식회사 Novel crystalline form of sitagliptin hydrochloride
KR100858848B1 (en) 2006-05-23 2008-09-17 한올제약주식회사 Pharmaceutical compositions and formulations of Metformin extended release tablets
WO2007144175A2 (en) 2006-06-16 2007-12-21 Lek Pharmaceuticals D.D. Pharmaceutical composition comprising hydrochlorothiazide and telmisartan
WO2007149797A2 (en) * 2006-06-19 2007-12-27 Novartis Ag Use of organic compounds
WO2007148185A2 (en) 2006-06-21 2007-12-27 Pfizer Products Inc. Substituted 3 -amino- pyrrolidino-4 -lactams as dpp inhibitors
EP2035395A2 (en) 2006-06-27 2009-03-18 Glenmark Pharmaceuticals S.A. Novel processes for the preparation of dpp iv inhibitors
US7919598B2 (en) 2006-06-28 2011-04-05 Bristol-Myers Squibb Company Crystal structures of SGLT2 inhibitors and processes for preparing same
EP2057160A1 (en) 2006-08-08 2009-05-13 Boehringer Ingelheim International GmbH Pyrrolo [3, 2 -d]pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus
CA2656847A1 (en) 2006-08-15 2008-02-21 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as sglt inhibitors and process for their manufacture
AU2007285827A1 (en) * 2006-08-17 2008-02-21 Wellstat Therapeutics Corporation Combination treatment for metabolic disorders
WO2008031750A2 (en) 2006-09-15 2008-03-20 F. Hoffmann-La Roche Ag Process for the preparation of pyrido[2,1-a]isoquinoline derivatives by catalytic asymmetric hydrogenation of an enamine
CN101516880B (en) 2006-09-15 2012-06-20 霍夫曼-拉罗奇有限公司 Process for the preparation of pyrido[2,1-a]isoquinoline derivatives comprising optical resolution of an enamine
CA2664095A1 (en) 2006-09-21 2008-03-27 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
EP2086991A1 (en) 2006-10-27 2009-08-12 Boehringer Ingelheim International GmbH CRYSTALLINE FORM OF 4-(ß-D-GLUCOPYRANOS-1-YL)-1-METHYL-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, A METHOD FOR ITS PREPARATION AND THE USE THEREOF FOR PREPARING MEDICAMENTS
US7956201B2 (en) 2006-11-06 2011-06-07 Hoffman-La Roche Inc. Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one
MY157828A (en) 2006-11-09 2016-07-29 Boehringer Ingelheim Int Combination therapy with sglt-2 inhibitors and their pharmaceutical compositions
WO2008062273A2 (en) 2006-11-20 2008-05-29 Cadila Pharmaceuticals Limited Solid oral dosage form having antidiabetic drug combination
UY30730A1 (en) 2006-12-04 2008-07-03 Mitsubishi Tanabe Pharma Corp CRYSTAL FORM OF HEMIHYDRATE 1- (B (BETA) -D-GLUCOPYRANOSIL) -4-METHYL-3- [5- (4-FLUOROPHENYL) -2-TIENYLMETHYL] BENZENE
JP2010516721A (en) 2007-01-26 2010-05-20 サノフィ−アベンティス Phenothiazine derivative, its production method and its use as a medicine
AR065033A1 (en) 2007-01-26 2009-05-13 Boehringer Ingelheim Int METHODS TO PREVENT AND TREAT NEURODEGENERATIVE DISORDERS
CA2677201C (en) 2007-02-01 2015-11-17 Takeda Pharmaceutical Company Limited Solid preparation comprising alogliptin and pioglitazone
WO2008093878A1 (en) 2007-02-01 2008-08-07 Takeda Pharmaceutical Company Limited Tablet preparation without causing a tableting trouble
WO2008101938A1 (en) 2007-02-21 2008-08-28 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture
JP2010519273A (en) 2007-02-21 2010-06-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Tetrasubstituted glucopyranosylated benzene derivatives, drugs containing such compounds, their use and methods for their production
ITFI20070042A1 (en) 2007-02-21 2008-08-22 Laboratori Guidotti Spa PHARMACEUTICAL FORMULATION AND COMPRESSED INCLUDING THIS FORMULATION.
CA2681092A1 (en) 2007-03-15 2008-09-18 Nectid, Inc. Anti-diabetic combinations comprising a slow release biguanide composition and an immediate release dipeptidyl peptidase iv inhibitor composition
TW200904454A (en) 2007-03-22 2009-02-01 Bristol Myers Squibb Co Methods for treating obesity employing an SGLT2 inhibitor and compositions thereof
TW200904405A (en) 2007-03-22 2009-02-01 Bristol Myers Squibb Co Pharmaceutical formulations containing an SGLT2 inhibitor
AU2008233548B2 (en) 2007-04-03 2011-12-01 Mitsubishi Tanabe Pharma Corporation Combined use of dipeptidyl peptidase IV inhibitor compound and sweetener
CN101754972A (en) 2007-05-18 2010-06-23 百时美施贵宝公司 Crystalline structure of SGLT2 inhibitor and preparation method thereof
UY31291A1 (en) 2007-08-16 2009-03-31 PHARMACEUTICAL COMPOSITION THAT INCLUDES A DERIVATIVE OF PIRAZOL-0-GLUCOSIDO
CL2008002427A1 (en) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Pharmaceutical composition comprising 1-chloro-4- (bd-glucopyranos-1-yl) -2- [4 - ((s) -tetrahydrofuran-3-yloxy) benzyl] -benzene combined with 1 - [(4-methylquinazolin- 2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (r) -aminopiperidin-1-yl) xanthine; and its use to treat type 2 diabetes mellitus.
CL2008002424A1 (en) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Pharmaceutical composition comprising a compound derived from pyrazole-o-glucoside; and use of the pharmaceutical composition for the treatment of diabetes mellitus, abnormal glucose tolerance and hyperglycemia, metabolic disorders, among others.
CL2008002425A1 (en) 2007-08-16 2009-09-11 Boehringer Ingelheim Int Pharmaceutical composition comprising an inhibitor of sglt2 and 1- (4-methyl-quinazolin-2-yl) methyl-3-methyl-7 - (- 2-butin-1-yl) -8- (3- (r) -amino- Piperidin-1yl) -xanthine, an iv dpp inhibitor and its use for the treatment of obesity and type 1 and 2 diabetes and complications thereof.
FR2920023B1 (en) 2007-08-16 2013-02-08 Sanofi Aventis 3-DISUBSTITUTED INDOL-2-ONE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF
AU2008290582B2 (en) 2007-08-17 2014-08-14 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
JP5596545B2 (en) 2007-09-10 2014-09-24 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Method for producing a compound useful as an inhibitor of SGLT
PL2597103T3 (en) 2007-11-16 2017-04-28 Novo Nordisk A/S Stable pharmaceutical compositions comprising liraglutide and degludec
CN101234105A (en) 2008-01-09 2008-08-06 北京润德康医药技术有限公司 Pharmaceutical composition containing diabetosan and vildagliptin and preparation thereof
CL2008003653A1 (en) * 2008-01-17 2010-03-05 Mitsubishi Tanabe Pharma Corp Use of a glucopyranosyl-derived sglt inhibitor and a selected dppiv inhibitor to treat diabetes; and pharmaceutical composition.
AU2009210641A1 (en) 2008-02-05 2009-08-13 Merck Sharp & Dohme Corp. Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor
MX2010009731A (en) 2008-03-04 2010-09-30 Merck Sharp & Dohme Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor.
US8551524B2 (en) 2008-03-14 2013-10-08 Iycus, Llc Anti-diabetic combinations
DK2280704T3 (en) 2008-03-31 2015-06-29 Cymabay Therapeutics Inc Oxymethylenarylforbindelser and uses thereof
PE20091730A1 (en) 2008-04-03 2009-12-10 Boehringer Ingelheim Int FORMULATIONS INVOLVING A DPP4 INHIBITOR
PE20100156A1 (en) 2008-06-03 2010-02-23 Boehringer Ingelheim Int NAFLD TREATMENT
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
MX2011001525A (en) 2008-08-15 2011-03-29 Boehringer Ingelheim Int Purin derivatives for use in the treatment of fab-related diseases.
CN102149407A (en) 2008-09-10 2011-08-10 贝林格尔.英格海姆国际有限公司 Combination therapy for the treatment of diabetes and related conditions
UY32177A (en) 2008-10-16 2010-05-31 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH INSUFFICIENT GLUCEMIC CONTROL TO WEIGHT THERAPY WITH DRUG, ORAL OR NOT, ANTIDIABÉTICO
WO2010045656A2 (en) 2008-10-17 2010-04-22 Nectid, Inc. Novel sglt2 inhibitor dosage forms
BRPI0923121A2 (en) 2008-12-23 2015-08-11 Boehringer Ingelheim Int Saline forms of organic compounds
AR074990A1 (en) 2009-01-07 2011-03-02 Boehringer Ingelheim Int TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY
TWI466672B (en) 2009-01-29 2015-01-01 Boehringer Ingelheim Int Treatment for diabetes in paediatric patients
JP5600328B2 (en) 2009-02-13 2014-10-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Pharmaceutical compositions comprising glucopyranosyldiphenylmethane derivatives, pharmaceutical dosage forms thereof, methods for their preparation and their use for improving glycemic control in patients
EP2395983B1 (en) 2009-02-13 2020-04-08 Boehringer Ingelheim International GmbH Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
EP2395988A2 (en) * 2009-02-13 2011-12-21 Boehringer Ingelheim International GmbH Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics
WO2010092123A1 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Sglt-2 inhibitor for treating type 1 diabetes mellitus, type 2 diabete mellitus, impaired glucose tolerance or hyperglycemia
UY32427A (en) 2009-02-13 2010-09-30 Boheringer Ingelheim Internat Gmbh PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM, PROCEDURE FOR PREPARATION, METHODS OF TREATMENT AND USES OF THE SAME
WO2010138535A1 (en) 2009-05-27 2010-12-02 Bristol-Myers Squibb Company Methods for treating type 2 diabetes in patients resistant to previous treatment with other anti-diabetic drugs employing an sglt2 inhibitor and compositions thereof
US20120100221A1 (en) 2009-06-02 2012-04-26 Ranbaxy Laboratories Limited Pharmaceutical compositions containing a combination of an antihistamine and a decongestant
US20120059011A1 (en) 2009-06-15 2012-03-08 Nicholas Birringer Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone
MX2012002942A (en) 2009-09-30 2012-04-11 Boehringer Ingelheim Int Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)be nzyl)benzene.
KR101813025B1 (en) 2009-09-30 2017-12-28 베링거 인겔하임 인터내셔날 게엠베하 Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
EP4209210A1 (en) 2009-10-02 2023-07-12 Boehringer Ingelheim International GmbH Pharmaceutical compositions comprising bi-1356 and metformin
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
LT2498758T (en) 2009-11-13 2018-11-26 Astrazeneca Ab Bilayer tablet formulations
PL2498759T3 (en) 2009-11-13 2019-03-29 Astrazeneca Ab Immediate release tablet formulations
CN107115530A (en) 2009-11-27 2017-09-01 勃林格殷格翰国际有限公司 Gene diabetes mellitus type utilizes the treatment of DPP IV inhibitor such as BI 1356
EP2547339A1 (en) 2010-03-18 2013-01-23 Boehringer Ingelheim International GmbH Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
EP2368552A1 (en) 2010-03-25 2011-09-28 Boehringer Ingelheim Vetmedica GmbH 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(r)-amino-piperidin-1-yl]-xanthine for the treatment of a metabolic disorder of a predominantly carnivorous non-human animal
US20140088027A1 (en) 2010-03-30 2014-03-27 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
KR101927068B1 (en) 2010-05-05 2018-12-10 베링거 인겔하임 인터내셔날 게엠베하 Sequential Combination Therapy by the Weight Reducing Treatment Followed by the DPP-4 Inhibitor
BR112012028091A2 (en) 2010-05-05 2016-08-02 Boehringer Ingelheim Int pharmaceutical compositions comprising pioglitazone and linagliptin
AU2011271124A1 (en) 2010-06-22 2013-01-10 Twi Pharmaceuticals, Inc. Controlled release compositions with reduced food effect
CN102971005A (en) 2010-06-24 2013-03-13 贝林格尔.英格海姆国际有限公司 Diabetes therapy
KR20130137624A (en) 2010-09-03 2013-12-17 브리스톨-마이어스 스큅 컴퍼니 Drug formulations using water soluble antioxidants
US20120283169A1 (en) 2010-11-08 2012-11-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
BR112013019026A2 (en) 2011-02-01 2016-10-04 Astrazeneca Uk Ltd pharmaceutical formulations including an amine compound
US20130035281A1 (en) 2011-02-09 2013-02-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
AR085689A1 (en) 2011-03-07 2013-10-23 Boehringer Ingelheim Int PHARMACEUTICAL COMPOSITIONS OF METFORMIN, LINAGLIPTINE AND AN SGLT-2 INHIBITOR
MX2013014135A (en) 2011-06-03 2014-01-23 Boehringer Ingelheim Int Sglt-2 inhibitors for treating metabolic disorders in patients treated with neuroleptic agents.
US20130035298A1 (en) 2011-07-08 2013-02-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
AR091739A1 (en) 2012-07-11 2015-02-25 Elcelyx Therapeutics Inc COMPOSITIONS AND METHODS TO REDUCE CARDIOMETABOLIC RISK
US20160000816A1 (en) 2013-04-05 2016-01-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
HUE041709T2 (en) 2013-04-05 2019-05-28 Boehringer Ingelheim Int Therapeutic uses of empagliflozin
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
ES2906115T3 (en) 2013-04-18 2022-04-13 Boehringer Ingelheim Int Pharmaceutical composition, treatment methods and uses thereof
US20160106677A1 (en) 2014-10-17 2016-04-21 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2017093419A1 (en) 2015-12-04 2017-06-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930141A (en) * 2004-03-16 2007-03-14 贝林格尔·英格海姆国际有限公司 Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof
WO2007093610A1 (en) * 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
WO2008055870A1 (en) * 2006-11-06 2008-05-15 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104203250A (en) * 2012-03-20 2014-12-10 勃林格殷格翰国际有限公司 Pharmaceutical composition comprising empagliflozin and antiobesity drug
CN104203250B (en) * 2012-03-20 2018-04-06 勃林格殷格翰国际有限公司 Comprising Yi Palie is net and the pharmaceutical composition of slimming drugs
CN104418847A (en) * 2013-09-10 2015-03-18 天津药物研究院 Process for preparing 4-(6-deoxidized-beta-D-glucopyranose)-2-[5-(4-fluorophenyl) thiophene-2-methyl]-1-methyl benzol
CN104739835A (en) * 2013-12-30 2015-07-01 中美华世通生物医药科技（武汉）有限公司 Novel pharmaceutical composition for treating diabetes
CN106176718A (en) * 2016-08-03 2016-12-07 上海延安药业有限公司 Compound recipe canagliflozin diformin tablet
CN112512530A (en) * 2018-07-19 2021-03-16 阿斯利康(瑞典)有限公司 Methods of treating HFpEF using dapagliflozin and compositions comprising dapagliflozin
CN113924096A (en) * 2019-03-25 2022-01-11 乔治全球健康研究院 Low dose triple combination formulation
CN111870694A (en) * 2020-07-20 2020-11-03 重庆大学 Use of SGLT2 inhibitors
CN111870694B (en) * 2020-07-20 2022-01-14 重庆大学 Use of SGLT2 inhibitors
CN114671839A (en) * 2020-12-25 2022-06-28 天地恒一制药股份有限公司 Solid form compound of dapagliflozin and preparation method and application thereof
CN114671839B (en) * 2020-12-25 2024-01-09 天地恒一制药股份有限公司 Dapagliflozin solid form compound and preparation method and application thereof
WO2024055932A1 (en) * 2022-09-13 2024-03-21 亚宝药业集团股份有限公司 Azacyclic compound, pharmaceutical composition thereof, and use thereof for preventing and/or treating disease

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